
==== Front
Signal Transduct Target Ther
Signal Transduct Target Ther
Signal Transduction and Targeted Therapy
2095-9907
2059-3635
Nature Publishing Group UK London

38172098
1723
10.1038/s41392-023-01723-x
Review Article
Lymphatic vessel: Origin, heterogeneity, biological functions and therapeutic targets
http://orcid.org/0000-0002-3222-9235
Hu Zhaoliang
Zhao Xushi
Wu Zhonghua
Qu Bicheng
Yuan Minxian
Xing Yanan ynxing@cmu.edu.cn

Song Yongxi yxsong@cmu.edu.cn

Wang Zhenning znwang@cmu.edu.cn

grid.412636.4 0000 0004 1757 9485 Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001 China
3 1 2024
3 1 2024
2024
9 98 7 2023
3 11 2023
23 11 2023
© The Author(s) 2023
2023
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Lymphatic vessels, comprising the secondary circulatory system in human body, play a multifaceted role in maintaining homeostasis among various tissues and organs. They are tasked with a serious of responsibilities, including the regulation of lymph absorption and transport, the orchestration of immune surveillance and responses. Lymphatic vessel development undergoes a series of sophisticated regulatory signaling pathways governing heterogeneous-origin cell populations stepwise to assemble into the highly specialized lymphatic vessel networks. Lymphangiogenesis, as defined by new lymphatic vessels sprouting from preexisting lymphatic vessels/embryonic veins, is the main developmental mechanism underlying the formation and expansion of lymphatic vessel networks in an embryo. However, abnormal lymphangiogenesis could be observed in many pathological conditions and has a close relationship with the development and progression of various diseases. Mechanistic studies have revealed a set of lymphangiogenic factors and cascades that may serve as the potential targets for regulating abnormal lymphangiogenesis, to further modulate the progression of diseases. Actually, an increasing number of clinical trials have demonstrated the promising interventions and showed the feasibility of currently available treatments for future clinical translation. Targeting lymphangiogenic promoters or inhibitors not only directly regulates abnormal lymphangiogenesis, but improves the efficacy of diverse treatments. In conclusion, we present a comprehensive overview of lymphatic vessel development and physiological functions, and describe the critical involvement of abnormal lymphangiogenesis in multiple diseases. Moreover, we summarize the targeting therapeutic values of abnormal lymphangiogenesis, providing novel perspectives for treatment strategy of multiple human diseases.

Subject terms

Lymphangiogenesis
Metastasis
https://doi.org/10.13039/501100001809 National Natural Science Foundation of China (National Science Foundation of China) 82202927 U22A20324 Wu Zhonghua Song Yongxi Funder: Excellent Youth Foundation of Liaoning Province Grant Reference Number: 2022-YQ-15issue-copyright-statement© West China Hospital, Sichuan University 2024
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pmcIntroduction

The lymphatic system is a vital component of the circulatory system and plays a crucial role in maintaining fluid homeostasis, lipid absorption and the immune response in the body. Comprising a vast network of lymphatic vessels, this intricate lymphatic system is a conduit for the transportation of lymph fluid, immune cells, and various macromolecules. Lymphatic vessels are lined with lymphatic endothelial cells (LECs) with distinct structures and functions in the hierarchical lymphatic network.1 Additionally, it is becoming increasingly clear that adult lymphatic vessels exposed to different organ-specific environments acquire distinct characteristics and in turn execute multiple tissue-specific functions. Abnormal lymphangiogenesis can be induced under pathological conditions, where it becomes an active player in the pathogenesis of several diseases, such as lymphedema, obesity and cancer.2 Recently, molecular and genetic techniques have propelled the identification of potential therapeutic targets to modulate lymphangiogenesis. In this review, we provide a comprehensive summary of lymphatic vessels, addressing their origin, heterogeneity, biological functions, and related therapeutic targets.

Historical research and milestone events of lymphangiogenesis

Milestone events of lymphatic vessel anatomy and function

The anatomy and function of lymphatic vessels have been investigated for more than 2000 years, and many researchers have contributed numerous landmark discoveries that have led to the gradual clarification of the structure and physiological function of lymphatic vessels.3,4 The earliest record of the lymphatic system is the finding of lymph nodes. In the 5th century B.C., Hippocrates first coined the term chylos (chyle) and observed lymphatic glands (lymph nodes) located in the armpits, near the ears, around jugular vessels, and spread through diverse locations in the abdominal cavity. Moreover, Hippocrates described a milky fluid, termed ichor (lymph fluid), flowing in the lumen of some vessels. Then, Aristotle (384–322 B.C.) identified some unique fibers between blood vessels and nerves that were filled with fluid, thereby first describing the anatomy of general lymphatic vessels.5 As interest increased, lymphatic vessels were clearly described in a variety of tissues. Herophilus (335–280 B.C.) and Erasistratus (304–250 B.C.) successively found chyliferous vessels inside the mesentery.6,7 In 1536, Massa (1485–1569) found some vessels (lymphatics) in fat tissue near kidneys (renal lymphatic vessels).8 Eustachi (1520–1574) found the vena alba thoracis (thoracic duct) during horse dissection but failed to identify the extended structure and function.9 In 1627, Gaspare Aselli found the venae albae aut lacteae (the gut lacteal, a specialized capillary lymphatics with a blind end that absorbs chylomicron from intestinal villi) in a dog in 1627.10 Immediately afterward, in 1628, Fabrice de Peiresc described lacteals in the human body.11

Then, researchers went beyond anatomical studies and began to investigate the role of lymphatic vessels in lymph drainage. Jean Pecquet (1624–1674) described the cisterna chyli (reservoir of the chyle) and thoracic duct and explained that lymph drained into the left subclavian vein via the thoracic duct not the liver.12 At approximately the same time, another lymphatic vessel that converge with the thoracic duct was also described. Olaus Rudbeck (1630–1702) found ducti hepatici aquosi (watery hepatic ducts), now known as hepatic lymphatic vessels. Rudbeck also found cardiac, renal, pulmonary, and peripheral lymphatic vessels in 1653.13,14 In the same year, another researcher, Thomas Bartholin (1616–1680), coined the term vasae lymphatica (lymphatics or lymphatic vessels) to describe the ducts conveying lymph fluid and distinguished mesenteric lymphatic vessels from hepatic lymphatic vessels, confirming that the lymph fluid from two different sources flows into the thoracic duct.15 Niels Stensen (1638–1686) specifically described that both the thoracic duct and left jugular lymphatic vessel delivered lymph into the angle between the duct of the left subclavian and internal jugular veins.4 Simultaneously, in 1675, Stensen also discovered cervical lymphatic vessels and lymph nodes.4 Subsequently, in 1701, Frederik Ruysch explored the morphology and function of lymphatic valves, which ensure the unidirectionality of lymph flow.16 Paolo Mascagni described lymphatic vessels in the human dura mater (meningeal lymphatic vessels) and lymph node-related lymphatic vessels in 1787.17,18

Despite the lack of advanced microscopy imaging techniques and specific lymphatic markers to stain, the striking findings and continued exploration laid the foundation for modern anatomy and knowledge about the function of lymphatic vessels. Herein, we clearly present the early research events and critical timepoints of lymphatic vessel discoveries in Fig. 1.Fig. 1 Milestone events of lymphatic vessel anatomy and function. Since the first discovery of chyle and lymph fluid at 5th B.C., some milestone findings have gradually revealed lymphatic vessel network and function in mammals. Created with Adobe Illustrator

Milestone events of lymphatic vessel origins and development

Early studies revealed the anatomy and function of mature lymphatic vessels, while modern research has been focused on the embryonic events of lymphatic vessel formations comprising origins and development (the specific events and timepoints of their discoveries are presented in Fig. 2). In 1902, Florence Sabin discovered the origin and development of lymphatic vessels by injecting India ink into pig embryos and then proposed the venous-origin theory of lymphatic vessels, which suggests that LECs sprout from veins and form the lymph sacs involved in general lymphatic vessel development.19 This researcher was the first to visualize the origin of lymphatic vessels and the development process. In contrast, in 1910, Huntington, McClure, and Kampmeier separately proposed a nonvenous theory of lymphatic vessel origin, suggesting that lymphatic vessels concentrically grow from isolated mesenchymal lymphangioblasts, coalesce into lymphatic sacs, and then connect to the venous system.20 These origin theories have been explored and verified for nearly a century. With the application of lineage tracing and other techniques in different animal models, the diversity of lymphatic vessel origins has been gradually revealed.Fig. 2 Milestone events of lymphatic vessels origins and development. In modern research (from 1902 to now), numerous researchers have gradually discovered the diverse origins and molecules of the lymphatic vessel development. These studies have doubtless initiated the understanding of heterogeneous development processes and regulatory mechanism of lymphatic vessels. VEGFR3 vascular endothelial growth factor receptor 3, PROX1 prospero homeobox protein 1, LYVE1 lymphatic vessel endothelial hyaluronan receptor 1, PDPN podoplanin, LEC lymphatic endothelial cell, FHF first heart field, SHF second heart field, ISL1 Islet 1, VAV1 vav guanine nucleotide exchange factor 1, PDGFRB platelet-derived growth factor receptor B, CSF1R colony-stimulating factor 1 receptor. Created with Adobe Illustrator

Martin Schneider and Annelii Ny supported the theory that lymphatic vessels originate from nonvenous cells and found that lymphangioblasts participate in the development of lymphatic vessels in avian wing bud and Xenopus laevis tadpole models in 1999 and 2005, respectively.21,22 The zebrafish is an optimal vertebrate model owing to its fast reproduction rate and ability of researchers to visualize their internal structures. In 2006, Axel M Küchler and Karina Yaniv respectively reported development and regulatory factors of lymphatic vessels in zebrafish models and supported the theory that lymphatic vessels are derived from embryonic veins.23,24 Additionally, mice are a proper mammalian models and have been used to show the process of lymphatic vessel development in different embryonic stages. In 2007, Sathish Srinivasan demonstrated that lymphatic vessels originated from venous endothelial cells (VeECs) by establishing prospero homeobox protein 1 (PROX1)-creERT2 model mice, PROX1 mainly drives the direct reprogramming of VeECs that form the functional lymphatic system that lasts a lifetime.25,26 René Hägerling showed the detailed process of embryonic lymphangiogenesis by applying ultramicroscopy to the study of whole-mount immunostained murine embryos in 2013.27 Hägerling found that lymphatic endothelial progenitor cells were selectively located on the dorsolateral wall of the cardinal vein, indicating that specific VeECs participate in lymphangiogenesis. Using lineage tracing and whole-mount immunostaining on different embryonic days, Oliver A. Stone found that the general lymphatic endothelium was derived mainly from paraxial mesoderm not lateral plate mesoderm. He further indicated that paraxial mesoderm-derived PAX3+ VeECs transdifferentiated into PROX1+ lymphatic endothelial progenitor cells in the cardinal veins and intersomitic veins. PAX3 is a marker for identifying myogenic progenitors in a subset of the somatic paraxial mesoderm, which could differentiate into muscular tissue and endocardium.28 Genetic lineage tracing in the past decade revealed the nonvenous cellular origins of a variety of organ-specific lymphatic vessels. Ines Martinez-Corral identified an isolated cell population involved in the formation of murine lumbar and dorsal midline dermal lymphatic vessels, showing another origin of dermal lymphatic vessels in 2015.29 Three years later, by applying genetic lineage tracing, Cathy Pichol-Thievend demonstrated that this progenitor cell population originated from a blood capillary plexus.30 Moreover, in 2015, Lukas Stanczuk found a population of hemogenic endothelium-derived c-Kit+ progenitor cells that may be involved in mesenteric lymphatic vessel development was discovered.31 Cardiac lymphatic vessels have also been shown to be derived from diverse cellular sources. In 2015, by using multiple Cre-loxp system-based lineage tracing, Linda Klotz determined that multiple populations of hemogenic endothelium-derived VAV1+/PDGFRB+/CSF1R+ progenitor cell contributed to cardiac lymphatic vessel development.32 Additionally, Kazuaki Maruyama and Ghislaine Lioux separately in 2019 and 2020 identified a population of second heart field-derived ISL1+ progenitor cells that participated in the formation of ventral cardiac lymphatic vessels.33,34 Two years later, Kazuaki Maruyama found that these ISL1+ progenitor cells originating from the cardiopharyngeal mesoderm differentiated into craniofacial and cardiac LECs.35

In the 1990s, a large number of studies on the regulatory factors and markers of lymphatic vessel have begun to emerge in the research field. In 1995, Kaipainen et al. discovered FLT4 gene (encoding vascular endothelial growth factor receptor 3, VEGFR3) becomes restricted in lymphatic endothelium during embryonic development.36 Subsequently, Kari Alitalo and Vladimir Joukov were the first researchers to isolate the ligand vascular endothelial growth factor C (VEGFC), the ligand for VEGFR2/VEGFR3 and a key factor in regulating LECs sprouting by activating VEGFR3 signaling, as proven by follow-up studies.37,38 In 1999, Guillermo Oliver and Jeffrey T Wigle demonstrated that PROX1 is the master regulator of lymphatic fate and regulates the expression of other transcription factors during embryonic lymphangiogenesis.39 At the same year, Silvana Breiteneder-Geleff discovered a transmembrane glycoprotein in podocytes, podoplanin (PDPN, encoded by T1α), which was specifically expressed in the endothelium of capillary lymphatics and was, therefore, the first lymphatic marker for immunolocalization and distinguishing the blood from lymphatic vessels.40 Simultaneously, Suneale Banerji determined that lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) is another specific lymphatic marker.41

These historical studies and milestone events reveal the diversity and heterogeneity of lymphatic vessel anatomy, function, and development and demonstrate the enthusiasm of these researchers for lymphatic vessel research.

Lymphatic vessel development and related regulatory signaling pathways

Lymphatic vessels in embryos undergo a stepwise developmental process, including lymphatic endothelial progenitor cell specification, LEC migration, and lymphatic vessel assembly and maturation.42 Lymphatic vessel development involves lymphangiogenesis and lymphvasculogenesis. Lymphangiogenesis, sprouting from preexisting lymphatic vessels/embryonic veins to form new lymphatic vessels, is the main developmental mechanism underlying the formation and expansion of lymphatic networks in an embryo.43,44 Another mechanism, termed lymphvasculogenesis, is the process by which various populations of nonvenous cells de novo express lymphatic markers and directly incorporated into new lymphatic vessels.43,45 Lymphatic vessel development is a highly conserved process across multiple species and relies on a stepwise and precise regulatory program.46 Currently available studies only observe localized lymphatic vessel anatomy in human fetuses, lacking dynamic developmental process.47–49 However, few studies have recorded the complete process of lymphatic vessel development. Due to ethical issues in using human fetuses, most studies of lymphatic vessel development and function have been carried out with other vertebrate animals, such as mice and zebrafish, and with contributions from these studies, the regulatory map of lymphatic vessel development is gradually being completed.50,51

Murine lymphatic vessel development and regulatory signaling pathways

General lymphatic vessel development and signaling pathways

Based on diverse studies with murine embryos, the timing and processes of lymphatic vessel development have been revealed.27 On approximately embryonic day 9.5–10.5 (E9.5–E10.5), a portion of VeECs located in the cardinal vein and intersomitic veins gradually transdifferentiate into lymphatic endothelial progenitor cells, which is the initial event in lymphatic vessel development.52 SRY-box transcription factor 18 (SOX18) and the chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII, encoded by NR2F2) are initially expressed in VeECs, which could synergistically activate PROX1 expression.53,54 Furthermore, COUP-TFII cooperates with PROX1 to upregulate the expression of VEGFR3, Neuropilin 2 (NRP2, a coreceptor with VEGFR3), and LYVE1.55,56 In turn, activated VEGFR3 contributes to the consistent expression of PROX1. The regulatory feedback loop further promotes lymphatic phenotype differentiation.57

At E10.5-E15.5, VEGFR3-expressing lymphatic endothelial progenitor cells sprout and form lymph sacs in response to extracellular VEGFC signaling, which triggers tip cells to leave veins and autonomously enter the surrounding mesenchyme.58 During this period, lymphatic endothelial progenitor cells differentiate into LECs and acquire migration and tube formation abilities. VEGFC is necessary and sufficient for prompting lymphatic endothelial progenitor cell budding and directed migration.38 At this stage, collagen and calcium binding EGF domains 1 (CCBE1) and a disintegrin and metallopeptidase with thrombospondin motifs 3 (ADAMTS3) are essential for the proteolytic cleavage of the active form of VEGFC.59,60 Moreover, NRP2 and VEGFR3 can jointly respond to VEGFC binding to regulate LEC migration.56 In addition, fibroblast growth factor (FGF), Adrenomedullin, and Hippo signaling play complementary roles in LEC proliferation and migration.61–63 In addition to biochemical pathways, mechanical force can activate lymphangiogenesis in this stage. The expression of the zinc-finger transcription factor GATA-binding protein 2 (GATA2) enhances VEGFR3 signaling in response to changes in tissue stiffness.64 Moreover, increased fluid volume could stimulate β1 integrin-mediated VEGFR3 signaling.65 Subsequently, lymph sacs separate from the cardinal vein via the action of platelet aggregation in response to c-type lectin-like receptor 2/PDPN signaling.66 Interestingly, platelet also maintain the homeostasis of lymphovenous valves.67 Lymphovenous valves, as the only connections between the blood and lymph circulatory systems, which have been gradually characterized, maintain unidirectional lymph drainage into veins. Especially, VEGFC activates the expression of YAP and TAZ to maintain PROX1 expression, which promote the lymphovenous valves and lymphatic valves development.68

From E15.5 to the early postnatal period, the primary lymphatic plexus gradually remolds into hierarchical lymphatic vessels with different features, and these vessels are classified into capillary lymphatic vessels, pre-collecting lymphatic vessels, and collecting lymphatic vessels. The transition of intercellular junctions and changes in cell morphology are fundamental to the initial functionality of lymphatic vessels (described “Capillary lymphatics”). Additionally, the maturation of collecting lymphatic vessels involves lymphatic valve morphogenesis and smooth muscle cell recruitment, which are the structural foundations for lymph transport.69 The constant shear stress caused by lymph flow can stimulate the LEC-expressed mechanosensory receptors, such as PECAM, VE-cadherin, PIEZO1, β1 integrin, VEGFR2, and VEGFR3.70 Downstream mechanotransduction signaling maintains the expression of key transcription factors, such as PROX1, GATA2, forkhead box P2 (FOXP2), and forkhead box C1/2 (FOXC1/2), which manipulate lymphatic valve formation.71–73 In addition to lymphatic valves, collecting lymphatic vessels transport lymph fluid by the action of coverage of smooth muscle cells. Smooth muscle cell recruitment is regulated by the expression of platelet-derived growth factor B (PDGFB), Reelin and MCP1 in LECs.74,75 Moreover, FOXC2 and Angiopoietin 2 (ANG2) could activate downstream signaling to maintain the normal pattern of smooth muscle cell coverage of vessels.73,76 In contrast, the Sema3A/NRP1/PlexinA1 axis prevents smooth muscle cells from covering valve-forming endothelial cells.77 We depict the developmental process of general lymphatic vessels in Fig. 3.Fig. 3 The schematic diagram of embryonic lymphatic vessel development. a Beginning at E9.5, VeECs, located at CV and ISVs, transdifferentiate into LEPCs. During E10.5-E15.5, the lymphatic plexus continues to sprouting and migrating, and expanding the primary lymphatic vessel network. Continuing from E15.5 until the early postnatal stage, the primary lymphatic plexus undergoes the maturation events to remodel into the hierarchical lymphatic vessels, comprising of capillary lymphatic vessels, pre-collecting lymphatic vessels, and collecting lymphatic vessels. Capillary lymphatic vessels sense interstitial pressure changes by anchoring filaments to control the opening of button-like junctions. The formation of pre-collecting and collecting lymphatic vessels requires for lymphatic valves morphogenesis and SMCs recruitment to drive lymph drainage; b At E10.5, upregulated VEGFR3 and NRP2 mediate LEPCs sprouting and LECs migration in response to VEGFC stimulation. VEGFC/VEGFR3 is an irreplaceable signaling regulates lymphatic vessel development; c The lymphovenous valve serves as the only connection of the lymphatic-venous system to prevent blood backflow. Platelet dynamically regulated lymphovenous hemostasis via interacting with LECs to activate CLEC2/PDPN signaling pathway to maintain platelet aggregation; d Under the stimulation of OSS, the differentiation of valve-forming cells prepares to proliferation, elongation, and protrusion. Moreover, ECM deposition and selective SMCs coverage further promote lymphatic vessel maturation. Ex embryonic day x, VeECs venous endothelial cells, CV cardinal vessel, ISVs intersomitic veins, LECs lymphatic endothelial cells, LEPCs lymphatic endothelial progenitor cells, VEGFC vascular endothelial growth factor C, VEGFR3 vascular endothelial growth factor receptor 3, NRP1/2 neuropilin 1/2, CLEC2 c-type lectin-like receptor 2, PDPN podoplanin, OSS oscillatory shear stress, MCP1 monocyte chemotactic protein 1, PDGFB platelet-derived growth factor B, ECM extracellular matrix, SMCs smooth muscle cells. Created with Adobe Illustrator

Organ-specific lymphatic vessel development and signaling pathways

Lymphatic vessels undergo a general development process mediated through biochemical and mechanical signaling pathways and gradually form a specialized lymphatic vessel network. To adapt to the physiological needs of different organs, lymphatic vessel development involves heterogeneous processes and responses to lymphangiogenic signaling.78 Therefore, we summarize the development process of organ-specific lymphatic vessels and regulatory signaling in Table 1. We also depict schematic diagrams of the murine organ-specific lymphatic vessel anatomy in Figs. 4–6.Table 1 Organ-specific lymphatic vessel development and regulatory signaling pathways in mouse

Organ-specific lymphatic vessels	Developmental stages and events	Regulatory signaling pathways	Reference	
Meningeal lymphatic vessels	P0–P28: Venous-origin lymphatic vessels start sprouting around the foramen magnum and gradually cover the most meninges of the central nervous system, and meningeal lymphatic vessel development is provided with the specific niches by dural sinuses, cerebral arteries, and central nerve bundles.	1. VEGFC/VEGFR3 signaling regulates meningeal lymphatic vessel development and maintains structural integrity.

2. Mechanical forces maintain the maturation and function of meningeal lymphatic vessels after birth, which is mediated by PLCγ2 involved in the CLEC2/PDPN signaling to control lymph flow.

	125,389–393	
Ocular lymphatic vessels	P0-P14: Ocular surface lymphatic vessels sprout from pre-existing lymphatic vessels and begin from the inner canthus, and then gradually develop into limbal and conjunctive lymphatic vessels following a nasal-to-temporal manner.

P1-P17: Schlemm’s canal derived from episcleral veins follows a similar developmental manner via sprouting and interconnecting into the vessel-like structure, and then endothelial cells express PROX1 but acquire mixed cell identity with partial vascular and lymphatic markers. Subsequently, Schlemm’s canal continues maturing and possesses a luminal structure with two layers of endothelial cells.

	1. VEGFC/VEGFR3 signaling mainly activates the ocular surface lymphatic vessels and Schlemm’s canal development.

2. ANG1/2 binding to TIE1/2 could enhance ocular surface lymphatic vessels and Schlemm’s canal development, meanwhile, ANG4 and SVEP1 are also involved in this regulatory pathway.

3. The shear stress-controlled transcription factor KLF4 physically binds to the first intron of the PROX1 coding sequence and induces PROX1 expression to maintain Schlemm’s canal identity and integrity.

	237,238,394–399	
Cardiac lymphatic vessels	E12.5-E14.5: Developmental cardiac lymphatic vessels sprout from both the outflow tract and sinus venous in a base-to-apex manner.

E14.5-E18.5: Diverse non-venous progenitor populations participate in cardiac lymphatic vessel development via lymphvasculogenesis.

P0-P15: Cardiac lymphatic vessels laterally and deeply sprout and cover most regions of the epicardium and myocardium of the postnatal heart.

	1. VEGFC/VEGFR3 signaling regulates the morphogenesis of cardiac lymphatic vessels, and transcription factors TBX1 and CCBE1 could be involved in this process.

2. VE-cadherin regulates cardiac lymphatic vessel development and postnatal structural stability via mediating Adrenomedullin signaling transactivating VEGFR3 by c-Src. Additionally, Adrenomedullin signaling could regulate RAP1-mediated lymphatic endothelial junction integrity.

	284,400–404	
Pulmonary lymphatic vessels	E11.5-E14.5: LECs migrate in a proximal-to-distal manner into the developing lung lobes, and then the primary lymphatic plexus expands along the bronchovascular bundles.

E18.5-P0: The pulmonary lymphatic vessel network has been widely distributed in the airways and lower respiratory bronchioles, as well as existing abut intralobular arterioles and small veins. Around birth, pulmonary lymphatic vessels rapidly function in response to the surge generation of interstitial fluid along the change of button-like junctions.

	1. VEGFC/VEGFR3 signaling mediates pulmonary lymphatic vessel development from the embryonic to the neonatal period.

2. At birth, transient expression of c-JUN can induce CDH13 and ATF3 expression, remodeling the conformation of the actin cytoskeleton and initiating lymphatic vessel drainage in response to high shear stress.

	405–407	
Hepatic lymphatic vessels	P1–P7: The primary hepatic lymphatic vessels appear at large superficial portal tracts.

P8–P21: The lymphatic vessels continuously sprout deeply and terminally distribute at the portal vein region, the hepatic vein region, and the hepatic capsule region.

	1. Heterozygous mutations of VEGFC/VEGFR3 delay hepatic lymphatic vessel development and disrupt the lymphatic vessel structure.

2. CHD4 raises the transcriptional activity of uPAR to activate plasmin, maintaining the development and structure of hepatic lymphatic vessels and lymphovenous valves.

	408–411	
Intestinal lymphatic vessels	E12-E13: The right subcardinal veins-derived LECs outgrow ventrolaterally to form retroperitoneal lymph sacs. Subsequently, mesenteric lymphatic vessels gradually sprout from retroperitoneal lymph sacs and go along the established mesenteric blood vessels at the left region of the dorsal mesentery.

E13.5: A population of the hemogenic endothelium-derived c-Kit+ progenitor cells incorporates into mesenteric lymphatic vessels via lymphvasculogenesis.

E14.5-E15.5: The mesenteric lymphatic vessels continue expanding and forming intestinal wall lymphatic vessels, filling the submucosa along the branch trail of the arteries.

E17.5-P10: The mesenteric lymphatic vessels sprout into the majority of the villus and form the mature lacteals.

	1. ANG/TIE and Adrenomedullin/CALCRL/ERK signalings respectively activate downstream cascades to stimulate intestinal lymphatic vessel development.

2. VEGFR3/PI3K signaling has a selective role in regulating intestinal lymphatic vessel development dependent on different regulatory subunits, including p110α, p85α, p55α, and p50α.

3. Some negative regulators stabilize intestinal lymphatic vessel development and integrity by antagonizing VEGFC/VEGFR3 signaling, including RASA1, CCM3, and Claudin-like proteins.

	31,113,412–418	
Renal lymphatic vessels	E14.5-E15.5: Renal lymphangiogenesis sprouts from the renal hilum based on the establishment of massive vascular networks.

E16.5-E18.5: The developing hilar lymphatic vessels continue remolding and extending towards the renal cortex. Meanwhile, some isolated LEC clusters participate in renal lymphatic vessel development via lymphvasculogenesis. Additionally, the ascending vasa recta, lymphatic-like vessels, are developing for lymph transport.

	1. VEGFC regulates renal lymphangiogenesis and lymphvasculogenesis contributing to renal lymphatic vessel development.

2. ANG1 and ANG2 synergistically act on TIE2 for the function and stability of the ascending vasa recta.

	419,420	
Dermal lymphatic vessels	E13.5-E16.5: Dermal lymphatic vessels continuously sprout from lateral sides towards the dorsal midline in the skin via lymphangiogenesis. Meanwhile, a population of blood capillary-derived PROX1+ cells is involved in dermal lymphatic vessel development via lymphvasculogenesis at lumbar and dorsal midline skin.	1. CCBE1/VEGFC signaling activates lymphatic endothelial progenitor cells sprouting from veins and blood capillaries to form dermal lymphatic vessels.

2. The DLL4/NOTCH1 signaling pathway regulates VEGFR3 expression in an EphrinB2-mediated manner to affect dermal lymphatic vessel development. Additionally, NOTCH4 has a distinct influence on regulating the dermal LEC migration and lymphatic vessel branching via activating different cascades.

	30,421,422	
Ovarian lymphatic vessels	P8.5-P12.5: The ovarian lymphatic vessels sprout from the hilum of the ovary, and then continuously sprout towards the ovarian mesenchyme.	1. Ovarian lymphatic vessels develop is mediated by VEGFC/VEGFR3 signaling in an ADAMTS1-dependent manner.

2. Follicle-stimulating hormone and estradiol regulate VEGFC/D/VEGFR3-mediated regional ovarian lymphangiogenesis.

	423–425	
Skeletal lymphatic vessels	Recently, existing of skeletal lymphatic vessel in physiological conditions has been first revealed, however, the process of skeletal lymphatic vessel development is rarely documented.	VEGFC/VEGFR3 signaling prompts skeletal lymphangiogenesis.	283	
LEC lymphatic endothelial cell, VEGFC vascular endothelial growth factor C, VEGFR3 vascular endothelial growth factor receptor 3, PLCγ2 phospholipase C gamma 2, ANG angiopoietin, CLEC2 c-type lectin-like receptor 2, PDPN podoplanin, TIE tunica interna endothelial cell kinase, PROX1 prospero homeobox protein 1, CHD4 chromodomain helicase DNA binding protein 4, uPAR urokinase-type plasminogen activator receptor, SVEP1 sushi von Willebrand factor type A EGF and pentraxin domain containing 1, KLF4 KLF transcription factor 4, TBX1 T-box 1, CCBE1 collagen and calcium binding EGF domains 1, CDH13 cadherin 13, ATF3 activating transcription factor 3, RAP1 Ras-related protein 1, RASA1 RAS p21 protein activator 1, CCM3 cerebral cavernous malformation 3, DLL4 delta like canonical Notch ligand 4, VE-cadherin vascular endothelial-cadherin, CALCRL calcitonin receptor-like receptor, ERK extracellular signal-regulated kinase, ADAMTS1 a disintegrin and metallopeptidase with thrombospondin motifs 1, PI3K phosphoinositide 3-kinase

Fig. 4 The lymphatic vessels in meninge and eyes. a The meningeal lymphatic vessels are mainly located at the dural region abut to the cranium, and developing along the cerebral vessels and nerves. Meningeal lymphatic vessels enter the nasal submucosal interstitium traveling through cribriform plate and form nasal lymphatic vessels extracranially, partly participating in the extracranial CSF drainage; b The meningeal lymphatic vessels exchange CSF with glymphatic system at subarachnoid space and eventually drain it into dcLNs; c SC abuts juxtacanalicular region of the TM, consisting of inner and outer wall constituted by heterogeneous endothelial cells. The inner wall could sense flow and transport aqueous humor into the SC and further drain to downstream episcleral veins; d The ocular surface lymphatic vessels originate from the nasal canthus and encircle laterally along the corneal limbus and the bulbar conjunctiva. CSF cerebrospinal fluid, dcLNs deep cervical lymph nodes, SC Schlemm’s canal, TM trabecular meshwork. Created with Adobe Illustrator

Fig. 5 The lymphatic vessels in heart, lung, liver, kidney, and intestine. a Cardiac lymphatic vessels develop from the extracardiac region and follow the basal-to-tip manner along the developing coronary arteries to the ventricles; b Pulmonary lymphatic vessels consists of interlobular, intralobular and pleural lymphatic vessels, and develop surround airway, blood vessels and developing alveoli; c Capillary lymphatic vessels of the portal tract region mainly absorb the lymph secreted into the Disse space and eventually drain through collecting lymphatic vessels into thoracic duct; d Capsular lymphatic vessels are located near the renal surface. Cortical capillary lymphatic vessels accompany the renal tubules, glomeruli and small arteries and run along the medullary collecting lymphatic network and are finally excluded from the kidney via the hilar lymphatic vessels; e The intestinal lymphatic vessels consist of mesenteric collecting lymphatic vessels, mucosal, submucosal, muscle lymphatic vessels, and lacteals. Created with Adobe Illustrator

Fig. 6 The lymphatic vessels in skin, ovary, and bone. a Skin lymphatic vessels, consisting of superficial and deep lymphatic vessel networks, are mainly located in the dermis and partly accompanied by dermal blood vessels. During E13.5 to E15.5, the primitive lymphatic plexus of the dorsally cervical region of skin begins to develop from the bilateral sides toward the midline of the back; b Ovarian lymphatic vessels develop along established blood vessels in the interstitium, which happened during the period of the first wave of follicular development; c Skeletal lymphatic vessels could develop at the sternum, femur, and tibia. And this part shows the skeletal lymphatic vessels go along the bone marrow of the long bones. Ex embryonic day x. Created with Adobe Illustrator

Zebrafish lymphatic vessel development and related signaling pathways

Because of their relatively transparent body, large number of progeny, and short developmental cycle, zebrafish have become an optimal animal model for observing the dynamic development of lymphatic vessels.79,80 Through the combined application of high-resolution imaging techniques and identification of lymphatic markers, the heterogeneous processes underlying lymphatic vessel development in zebrafish have been gradually elucidated in the past decade.79 Although the main lymphangiogenic signaling network is conserved across mammals, lymphatic vessel development is regulated by specific molecules and signaling pathways in zebrafish. Therefore, we summarize the heterogeneous development processes of lymphatic vessels (Fig. 7) and the significant molecules and signaling pathways in zebrafish (Table 2).Fig. 7 The schematic of lymphatic vessels development in zebrafish. a Zebrafish possess an extensive lymphatic vessel network throughout the body. Specialized lymphatic vessels development in zebrafish includes facial lymphatic vessel development (b), intestinal lymphatic vessel development (c), and trunk lymphatic vessel development (d); b The facial lymphatic vessels of zebrafish undergo a step-wise assembly from 1.5 dpf to 4 dpf. The FLS are derived from the CCV beginning to form along the PHS. Subsequently, a group of ETV2-expressing cells, known as VAL, begin to fuse with the lymphatic sprouts to form the LFL along the PHS. The LFL then begins to bud out to form a complex facial lymphatic vessels including the OLV, LAA, and MFL; c The development of intestinal lymphatic vessels proceeds from 3 dpf–15 dpf. At 3 dpf-4 dpf, LECs sprout from the PCV to the ventral and bilateral sides, respectively to form segmental lymphatic vessels, which subsequently interconnect to form L-SIL, R-SIL. The SILs first bud toward the right side of the abdomen along the vascular network to form UR-IL and IR-IL. Finally, the lymphatic vessel network continues to expand follow the left vascular track to form UL-IL and LL-IL and take up intestinal lymph; d The formation of trunk lymphatic vessels is the earliest event of embryonic lymphatic vessel development in zebrafish, budding from the PCV to form the ISLV along the trajectory of the ISVs, and subsequently sprouting ventrally and dorsally to form the DLLV and TD, respectively. Dpf day postfertilization, CCV common cardinal vein, PHS primary head sinus, FLS facial lymphatic sprouting, VAL ventral aorta lymphangioblast, LFL lateral facial lymphatic vessel, OLV otolithic lymphatic vessel, ETV2 ETS variant transcription factor 2, LAA lymphatic branchial arches, MFL medial facial lymphatic vessels, PCV posterior cardinal vein, L-SIL the left supraintestinal vessel, R-SIL the right supraintestinal vessels, UR-IL upper-right intestinal lymphatics, LR-IL lower-right intestinal lymphatics, UL-IL upper-left intestinal lymphatics, LL-IL lower-left intestinal lymphatics, ISLV intersegmental lymphatic vessel, aISV arterial intersegmental vessels, vISV venous intersegmental vessel, PAC parachordal line, DA dorsal aorta, DLAV dorsal longitudinal anastomotic vessel, HM horizontal myoseptum, DLLV dorsal longitudinal lymphatic vessel, TD thoracic duct. Created with Adobe Illustrator

Table 2 Molecules and related signaling pathways of lymphatic vessel development in zebrafish

Molecules	Roles and effects on lymphatic vessel development	Signaling pathways	Reference	
PROX1	A transcription factor, which initiates LEPC transdifferentiation and continuously regulates lymphatic vessel development.	PROX1 induces LEC markers (VEGFR3, TBX1, CDH6, and CDN11b) expression and interplays with diverse downstream cascades (for example VEGFC/VEGFR3).	426–428	
VEGFC	The ligand of VEGFR3, which regulates LEPC transdifferentiation as well as LEC sprouting and migration.	VEGFC selectively stimulates the downstream cascades of VEGFR3 in a context-dependent manner and maintains PROX1 expression of LEPC via activating MEK/ERK signaling.	23,82	
VEGFD	The ligand of VEGFR2, which regulates LEC sprouting and migration in zebrafish heads.	VEGFD binding to VEGFR2 supplements the role of VEGFC/VEGFR3 signaling.	429–431	
ADAMTS2/3/14	Extracellular matrix proteins, which regulate LEC migration.	ADAMTS3 and ADAMTS2/14 proteolytically process immature VEGFC to activate VEGFR3.	432,433	
CCBE1	An extracellular matrix protein, which regulates LEC migration to enhance lymphatic vessel development.	CCBE1 cooperating with ADAMTS3 activates VEGFC/VEGFR3 signaling via proteolytic activation of immature VEGFC.	84,432,434	
SOX18	A transcription factor, which regulates LEC sprouting and migration to enhance TD formation.	SOX18 directly interacts with VEGFC to activate the downstream cascades.	426,435	
SOX17	A transcription factor, which negatively regulates LEPC transdifferentiation and realizes lymphatic-to-blood vascularization in zebrafish anal fin.	SOX17 negatively regulates the lymphatic identity via suppressing PROX1 expression.	436	
HHEX	A transcription factor, which regulates LEPC transdifferentiation as well as LEC sprouting and migration.	HHEX is involved in the VEGFC/VEGFR3/PROX1 cascade to affect early lymphatic vessel development.	437	
MAFB	A Transcription factor of the MAF family, which regulates LEC migration, sprouting, and patterns of facial lymphatic vessel development. MAFBa regulates LEPC sprouting and MAFBb patterns trunk lymphatic vessel development.	Transcription factor SOX7/18 stimulates the MAFBa/b expression, which is a downstream target of VEGFC/D signaling.	438	
GATA2	A transcription factor, which regulates lymphatic valve formation and facial lymphatic vessel development.	Under the stimulation of shear stress, GATA2 activates downstream target genes (PROX1, FOXC1/2, NFATC1).	439	
EFNB2	The ligand of EPHB4, which initiates lymphatic valves and lymphovenous valve morphogenesis.	EFNB2/EPHB4/RASA1 axis induces PROX1 expression to promote the differentiation of valve-forming cells via inhibition of ERK signaling.	440	
WNT5	A member of the WNT family, which regulates LEPC transdifferentiation.	WNT5b upregulates PROX1 expression at the specialized niche within the cardinal vein via activating the canonical WNT/β-catenin signaling.	81	
CXCL12	A chemokine ligand, which regulates the LEC directed migration to assemble trunk lymphatic vessels.	CXCL12a/b binding with CXCR4a/b regulates LEC migration activity.	86,441	
BMP2	A member of the BMP family, which negatively regulates LEPC transdifferentiation and proliferation.	BMP2 signaling stimulates miR-31 and miR-181a expression in an SMAD-dependent manner and then reduces PROX1 expression.	442,443	
DLL4	The ligand of NOTCH signaling, which regulates LEC sprouting and migration to promote TD and PLs development.	DLL4 activates NOTCH1b or NOTCH6 signaling.	444	
Plexin D1	The receptor of Semaphorin 3AA/3 C, which negative regulates LEC sprouting and migration to inhibit facial lymphatic vessel formation.	Plexin D1 competitively inhibits VEGFC/VEGFR3/ERK signaling.	445	
Regulators	Role and function in zebrafish lymphangiogenesis	Signaling pathways	Reference	
Apelin	The ligand of APLNR, which patterns normal TD and PLs development and maintains LEC proliferation.	Apelin signaling selectively activates AKT1/2 phosphorylation.	446	
RASGRP1	A member of the RASGRP family, which regulates LEC sprouting and migration.	RASGRP1 possibly affects the downstream effectors of VEGFR3 signaling to enhance the RAS/ERK signaling pathway.	447	
PAR1	A kind of G-protein-coupled receptor, which regulates LEPC transdifferentiation.	Noncanonical MMP13b/PAR1/GNAI2a signaling pathway activates VEGFR3 expression which stimulates the phosphorylation of ERK1/2 to induce PROX1a expression in venous endothelial cells.	448	
CD146	A cell adhesion molecule, which regulates LEC proliferation, sprouting, and migration.	CD146 respectively activates p38 kinase and ERK signaling in response to VEGFC.	449	
SVEP1	An extracellular protein, which regulates LEC sprouting and migration to maintain the development and structure integrity of facial lymphatic vessels.	SVEP1 binds with TIE1 to activate the downstream cascades.	450	
GRB2	An adapter protein, which regulates LEC sprouting and migration to selectively promote meningeal lymphatic vessel development.	GRB2b genetically interacts with VEGFR3 to activate the downstream cascades.	451	
PKD1	A transmembrane protein, which regulates LEC migration and remolding later to maintain TD formation.	PKD1a partly interacts with WNT5a to regulate LEC sprouting from the horizontal myoseptum.	452,453	
Synectin	A scaffold protein, which regulates LEC sprouting and migration to form TD.	Synectin stimulates VEGFR3 and NRP2a to activate downstream signaling.	454	
YAP1	An effector of Hippo signaling, which stimulates LEPC proliferation and sprouting.	YAP1 is dependent on VEGFC to activate downstream signaling.	455	
DDX21	A kind of RNA helicase, which balances ribosome biogenesis and the cell cycle to regulate LEPC sprouting and migration.	DDX21 inhibits p53 and p21 expression to enhance VEGFC-mediated lymphangiogenesis.	456	
Netrin1a	A guidance protein, which regulates LEC sprouting and migration to form TD and PLs.	Netrin1a activates downstream DCC-mediated axon guidance cues for lymphangiogenesis.	457	
NOVA2	A RNA-binding protein, which regulates LEPC transdifferentiation.	NOVA2 inhibits the PROX1 expression via negatively regulating the pre-mRNA splicing of the MAPK/ERK signaling.	458	
VASH1	A kind of Carboxypeptidase, which regulates LEPC transdifferentiation and proliferation to enhance secondary sprouting for trunk lymphatic vessel development.	VASH1 mediates tubulin detyrosination to control the number of secondary sprouting cells.	459	
miR-126	A member of miRNAs, which regulates LEC sprouting and migration.	MiR-126a induces the expression of CXCL12a and enhances chemokine signaling and VEGFR3 expression.	460,461	
miR-204	A member of miRNAs, which regulates lymphatic vessel development.	MiR-204 acts on the transcription factor NFATC1.	462	
miR-182	A member of miRNAs, which regulates LEC sprouting and migration to form the TD and PLs.	MiR-182 negatively regulates JUNB-mediated the FOXO1 expression.	463	
LEPC lymphatic endothelial progenitor cell, LEC lymphatic endothelial cell, TD thoracic duct, PLs parachordal lymphangioblasts, PROX1 prospero homeobox protein 1, VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor, ERK extracellular signal-regulated kinase, MAPK mitogen-activated protein kinase, TIE tunica interna endothelial cell kinase, TBX1 T-box 1, CDH6 cadherin 6, ADAMTS a disintegrin and metallopeptidase with thrombospondin motifs, CCBE1 collagen and calcium binding EGF domains 1, SOX SRY-related HMG-box, HHEX hematopoietically expressed homeobox, MAFB V-maf musculoaponeurotic fibrosarcoma oncogene homolog B, FOXC forkhead box C, NFATC1 nuclear factor of activated T-cells cytoplasmic 1, GATA2 GATA-binding protein 2, EFNB2 ephrin B2, EPHB4 ephrin type B receptor 4, RASA1 RAS p21 protein activator 1, WNT5b Wnt family member 5b, CXCL12 C-X-C motif chemokine 12, CXCR4 C-X-C chemokine receptor type 4, BMP2 bone morphogenetic protein 2, DLL4 delta like canonical Notch ligand 4, RASGRP1 RAS guanyl releasing protein 1, AKT protein kinase B, PAR1 protease-activated receptor 1, MMP matrix metalloproteinase, GNAI2 G protein subunit alpha i2, SVEP1 sushi von Willebrand factor type A EGF and pentraxin domain containing 1, GRB2 growth factor receptor bound protein 2, PKD1 polycystic kidney disease 1, NRP2 neuropilin 2, YAP1 Yes-associated protein 1, DDX21 DEAD-box helicase 21, NOVA2 Neuro-oncological ventral antigen 2, VASH1 vasohibin 1, DCC Deleted in colorectal cancer (the Netrin1 receptor), miRNAs microRNAs, FOXO1 forkhead box O1

Early lymphatic vessel development occurs during the first day 5 postfertilization (dpf). Similar to mammals, the posterior cardinal vein is the origin of lymphangiogenesis.81 Between hour 30 and 34 postfertilization (hpf), a population of bipotential progenitor cells (also known as lymphangioblasts) generates two kinds of endothelial cells, VeECs and PROX1-expressing lymphatic endothelial progenitor cells.82 In particular, VEGFC is the key factor that regulates the division of cell identity, and it also triggers PROX1 expression.82 Moreover, the role of PROX1 in initiating the transdifferentiation of VeECs into lymphatic endothelial progenitor cells is conserved in both zebrafish and mammals.82 At 1.5 dpf-2 dpf, LECs dorsally sprout toward the horizontal myoseptum, forming a population of LECs known as parachordal lymphangioblasts (or parachordal line). CCBE1/VEGFC/VEGFR3 signaling regulates LEC sprouting and migration.83,84

At 2.5 dpf-4 dpf, lymphatic vessel sprouts from the parachordal lymphangioblasts begin to migrate dorsally and ventrally along arterial intersegmental vessels not venous intersegmental vessels, forming intersegmental lymphatic vessels.85,86 Subsequently, LECs on the dorsal and ventral sides of the intersegmental vessels migrate rostrally and caudally and ultimately interconnect, forming the two trunk lymphatic vessels, namely, the dorsal longitudinal lymphatic vessel (abutting the dorsal longitudinal anastomotic vessel) and thoracic duct (abutting the posterior cardinal vein).87,88 We show the process of mainly trunk lymphatic vessel development in Fig. 7 and describe the related regulatory signaling pathways involved in LEC sprouting and migration in Table 2.

Between 5 dpf and 7 dpf, LECs begin to emerge from the intersegmental lymphatic vessels (the third trunk lymphatic vessel) and extend rostrally and caudally along the horizontal myoseptum to gradually form parachordal lymphatic vessels.80 Subsequently, parachordal lymphatic vessels continue to expand laterally during zebrafish development and form intercostal lymphatic vessels at approximately 15 dpf.80 Parachordal lymphatic vessels and intercostal lymphatic vessels become lateral lymphatic vessels in zebrafish. Through sophisticated signaling mechanisms, VEGFC/VEGFR3 is the key interaction that triggers the signaling cascade to activate LECs continuously. Interestingly, the homeobox transcription factor HOXC9 supports the expression of stabilin 2 to maintain the normal formation of thoracic duct and parachordal lymphangioblasts, and another homologous protein, stabilin 1, plays a similar role in promoting zebrafish lymphangiogenesis in a HOXC9-independent manner.89

In this developmental period, organ-specific lymphatic vessel development simultaneously occurs in the head and intestine of zebrafish.80,90 We depict the process of organ-specific lymphatic vessels by development stages in Fig. 7. Further studies should be conducted to verify the specific function of lymphangiogenic signaling pathways in organ-specific lymphatic vessel development and biological capacity.

Biological functions of lymphatic vessels and related regulatory signaling pathways

Anatomy and structure of the lymphatic vessel network

The lymphatic system includes primary lymphoid organs (the bone marrow and thymus), secondary lymphoid organs (the lymph nodes, spleen, and mucosal-associated lymphoid tissue), and lymphatic vessels that connect all lymphoid organs.91 The lymphatic vessel network is composed of capillary lymphatics, pre-collecting and collecting lymphatics.92 Additionally, the cell-cell junctions (button- and zipper-like junctions) are important for functionally specialized capillary and collecting lymphatics (Fig. 8).Fig. 8 Anatomy of the lymphatic system. a The lymphatic system includes the primary and secondary lymphoid organs and lymphatic vessels, providing a one-way drainage route from all tissues back ultimately to the blood circulation via the great veins in the neck. In the primary lymphoid organs (bone marrow and thymus), immune cell production and maturation takes place, whereas secondary lymphoid organs (lymph nodes, spleen, and mucosa-associated lymphoid organs such as Peyer’s patch, tonsils, and adenoids) are the sites for lymphocyte activation; b The thoracic duct is responsible for the lymph drainage coming from most of the body with the exception of the right side of the head and neck, the right side of the thorax and the right upper limb where drain lymph primarily into the right lymphatic duct; c–e The spleen, the Peyer’s patch and lymph nodes are highly organized structures with segregated B-cell and T-cell zones to optimize the induction of adaptive immune responses; f The capillary lymphatics drain downstream into the collecting lymphatics. Capillary LECs are interconnected via discontinuous junctions allowing the fluid to enter the system passively. Collecting LECs present with continuous junctions. Collecting lymphatics differ from capillary lymphatics by possessing intraluminal valves, LSMCs and a continuous basement membrane. LSMCs lymphatic smooth muscle cells, LECs lymphatic endothelial cells, GC germinal center. Created with Adobe Illustrator

Capillary lymphatics

Capillary lymphatics (also called initial lymphatics) consist of a single layer of loosely connected LECs without a continuous basement membrane and are covered by pericytes or smooth muscle cells.93 They are blind-ended vessels and are connected by anchoring filaments to the interstitial tissue. Overlapping endothelial cells build flap-like mini-valves, ensuring one-way interstitial fluid, macromolecule, and immune cells flow into the vessels. These capillary lymphatics in the most tissues are interconnected through discontinuous button-like junctions. Additionally, the integrity of LEC junctions is regulated by two different types of cell-cell junctions: adherens junctions and tight junctions.

The button-like junctions of the capillary lymphatics are formed by adherens junction proteins, including VE-cadherin,94 p120-catenin, and catenin, which bind to each other and the actin cytoskeleton. Tight junctions are formed by transmembrane proteins, such as claudin-5 and occludin, and the cytoplasmic protein ZO-1, which regulate paracellular permeability,91 and junctional adhesion molecule and endothelial cell-selective adhesion molecule, which are involved in leukocyte transmigration. The ANG/tunica interna endothelial cell kinase 2 (TIE2) signaling pathway is indispensable for the formation of button-like junctions within capillary lymphatics.95 In lacteals, VEGFC-VEGFR2/3-delta-like 4 (DLL4)-NOTCH signaling is crucial for constant regeneration and maintenance of button junctions.96

Collecting lymphatics

Capillary lymphatics drain into pre-collecting lymphatic vessels and merge with larger collecting lymphatics. Collecting lymphatic vessels contain valves that regulate the unidirectional flow of lymph with the coordinated contraction of smooth muscle cells facilitating the transport of lymph into the bloodstream.97 Tissue fluid transported by collecting lymphatics ultimately drains into the thoracic duct and right lymphatic duct, which discharge lymph into the common opening of the jugular and subclavian veins known as the venous angle.98

In collecting lymphatics, LECs are continuously connected through zipper-like junctions and are enveloped by specialized smooth muscle cells that contract to assist lymph flow.93 During mouse embryonic development, the transformation from continuous zipper-like junctions (formed at E12.5-E16.5) to button-like junctions begins at E17.5 and is mostly complete by postnatal day (P) 28.99 Therefore, zipper-like junctions are regulated in a manner similar to that of button-like junctions, however, some mechanisms that specifically regulate zipper-like junctions are described below. RhoA/ROCK signaling is essential for LEC junction formation in lacteals, lymphatic valves, and collecting vessels. Transcription factors FOXC1 and FOXC2 are required for maintaining LEC junction integrity in lymphatic valves, collecting vessels, and dermal lymphatics.92 Recent studies identified several other major signaling pathways that control tight junction localization and lymphatic vessel integrity, including EphrinB2/EphB4 and S1PR1.91

Biological functions of lymphatic vessels

The general functions of lymphatic vessels in fluid absorption and transport, as well as immunosurveillance, are well understood. However, accumulating evidence indicates that lymphatic vessels play active and versatile roles in an organ-specific manner during homeostasis and multiple disease processes.100 We provide a brief overview of the novel discoveries of organ-specific functions of adult mammalian lymphatic vessels, including immunosurveillance after pathogen invasion, transport of dietary fat, and drainage of cerebrospinal fluid and aqueous humor.

Lymph absorption and transport

Lymphatic vessels play crucial roles in the uptake and transport of multiple substances to maintain tissue fluid homeostasis, such as lipids, proteins, and immune cells in the body, which present diverse characteristics in different organs.101 Studies have suggested that both passive paracellular and active transcellular transport mechanisms may contribute to lymph absorption.102 Moreover, lymphatic vessels have an active role in draining excess interstitial fluid from organs and serving as conduits for immune cell trafficking to lymph nodes. The lymphatic pump undergoes phasic contractions generated by lymphatic smooth muscle cells to realize lymph transport, and lymphatic valves ensure one-way lymph transport. When upstream valves open, diastolic filling causes vessel wall stretching, increasing vessel volume and pressure. Systole subsequently begins with the rapid contraction of the lymphatic muscle and closure of the upstream valve (Fig. 9). To give readers a clear understanding, we summarize the absorption and transport functions of lymphatic vessels in diverse organs as follows.Fig. 9 Lymph absorption and transport. a Capillary lymphatics comprise a single layer of loosely connected LECs lacking a continuous basement membrane and perivascular mural cells. LECs within capillary lymphatics are interconnected through discontinuous button-like junctions that facilitate the uptake of interstitial fluid, macromolecules and immune cells which are released by the blood capillary; b Collecting lymphatics have a period of brisk contraction (systole) and a period of relaxation (diastole) between each phasic contraction. Each lymphangion, defined as the segment between two valves, can typically exhibit systole and diastole. When a lymphangion is relaxed, the inflow (or upstream) valve will open (given sufficient inflow pressure). During systole, the phasic contraction pushes the lymph, but the inflow valve closes, so that lymph is forced forward through the outflow valve. LECs lymphatic endothelial cells. Created with Adobe Illustrator

Lymph absorption and transport in meningeal lymphatic vessels

Although the brain parenchyma is devoid of lymphatic vessels, the rapid clearance of cellular debris and metabolic products in the central nervous system is attributable to the glymphatic system and meningeal lymphatic vessels.103 The glymphatic system is composed of three essential components: the para-arterial cerebrospinal fluid influx channel, the para-venous interstitial fluid efflux channel, and the water channel aquaporin-4 in astrocytes that connect these channels.103 Cerebrospinal fluid flows into the brain through the para-arterial space and exchanges with interstitial fluid via aquaporin-4; this type of exchange drives metabolite and interstitial fluid into the para-venous space and then into the cerebrospinal fluid circulatory system or directly through the capillary lymphatics into the cervical lymphatics. In particular, the glymphatic system transports lipids within the brain. Excess cholesterol in the brain is eliminated through hydroxylation to 24-hydroxycholesterol by Apolipoprotein E concentrated in astrocytes.

In addition to the glymphatic system, meningeal lymphatic vessels are involved in the elimination of cellular debris and waste products. Dorsal meningeal lymphatic vessels transport macromolecules and cells along the superior sagittal and transverse sinuses. Basal meningeal lymphatic vessels possess lymphatic valves without smooth muscle cells, thereby acquiring a pre-collector phenotype.104 Dysfunction of meningeal lymphatic vessels potentially contributes to the onset and progression of Alzheimer’s disease by disrupting the clearance of pathological proteins such as amyloid-β and tau protein, which we will discuss in “Abnormal lymphangiogenesis in human diseases”.

Lymph absorption and transport in ocular lymphatic vessels

The ocular surface lymphatic system and Schlemm’s canal regulate lymph absorption and transport in ocular lymphatic vessels. Regarding the ocular surface lymphatic system, lymphatic vessels have been identified in the corneal limbus and conjunctiva of mice and humans.105 Ocular surface lymphatic vessels are characterized by button-like junctions, an oak leaf-like shape, and luminal valves with features similar to those of capillary lymphatics and pre-collecting lymphatic vessels.106

Schlemm’s canal is an endothelial cell-lined vessel encircling the cornea and abutting the juxtacanalicular region of the trabecular meshwork.107 As a special structure regulating intraocular pressure, Schlemm’s canal drains aqueous humor into aqueous and episcleral veins.108 Yang et al. described a luminal structure called the lymphatic bridge that connects Schlemm’s canal to ocular surface lymphatic vessels, which allows aqueous humor outflow to the conjunctival lymphatic pathway. This finding suggested, for the first time, that the two lymphatic drainage systems are physically connected, expanding the knowledge of the aqueous humor pathway.109

Lymph absorption and transport in intestinal lymphatic vessels

Intestinal lymphatic vessels mediate distinct functions in fat absorption, intestinal homeostasis, and peripheral fat transport. Lymphatics continuously deliver nutrients to tissues. Dietary lipids are packaged into chylomicrons in the small intestines and transported via lacteals (capillary lymphatics in the small intestine), where they mix with lymph to become chyle. Mesenteric lymphatic vessels and cisterna chyli carry chyle through the thoracic duct and into the venous circulation.110 Defects in lacteals can cause problems with lipid uptake in the intestine. VEGFR2/VEGFR3 signaling, which is mediated through DLL4/NOTCH, is important for lacteal function maintenance. The deletion of DLL4 in lymphatics led to lacteal atrophy and an increase in the number of zipper junctions, resulting in the inability of the tissues to take up chylomicrons.111 Interestingly, VEGFA/VEGFR2 signaling also leads to a shift from the establishment of button-like junctions to that of zipper-like junctions in lacteals.112 Notably, lacteal atrophy caused by postnatal deletion of VEGFC impaired the absorption of lipids and led to steatorrhea.113

Although the small intestine is generally considered an absorptive organ, it can be induced to secrete fluids, causing diarrhea, under certain conditions.114 Intestinal lymphatics are important for fluid absorption, especially after a meal. Lymphatics also appear to participate in peripheral tissue lipid balance, and recent studies have shown that they are critical for reverse cholesterol transport. When high-density lipoprotein transports cholesterol out of cells and into peripheral tissues, lymphatic vessels conduct the particles into the bloodstream and back to the liver for excretion through feces.115 In mice, obstruction of lymphatic vessels impaired reverse cholesterol transport116 and led to increased atherosclerotic plaque formation.117

Lymphatic vessels in immunity

Lymph node lymphatic vessels in coordinating immune responses

Peripheral lymphatic vessels transport antigens and immune cells to draining lymph nodes, fostering an immune response.100 In mature lymph nodes, lymphatic vessels and specialized high endothelial venules that are indispensable for the trafficking of naïve lymphocytes into the paracortex of the lymph node,118 contributing to the adaptive immune response.119 Lymph node LECs contribute to immune response directly by antigen archiving and presentation. Antigen archiving in proliferating lymph node LECs can be directly transferred to other cells, for example, to migratory CD11c+ dendritic cells.120 Antigens can also be released from dying LECs and subsequently transferred to Batf3-dependent migratory dendritic cells. Antigens can be presented by LECs to immune cells through the MHC (comprising MHCI and MHCII).121

LECs in different regions can guide immune cell trafficking and positioning within lymph nodes by expressing specific molecules.122 For instance, LECs create a chemokine (C-C motif) ligand 21 (CCL21) gradient that facilitates the migration of dendritic cells into the lymph node medulla.123 Additionally, S1P gradients, formed by medullary LECs, are necessary for B and T-cell egress into efferent lymphatics and subsequent lymphocyte recirculation. LECs establish a niche for subcapsular sinus and medullary macrophage homing and maintenance. Lymph node LECs serve as major sources of the macrophage pro-survival factor colony-stimulating factor-1, with RANK receptor-expressing LECs inducing colony-stimulating factor-1 expression by interacting with CCL19+ marginal reticular cells, producing RANKL (Fig. 10).124Fig. 10 Compartmentalized functions of LN LECs. a Decoy CCL21 receptor CCRL1 produced by cLECs creates a CCL21 gradient and regulates intranodal migration of CCR7-expressing DCs; b The expression of CSF1 in LECs is maintained by RANK expressed on LECs, which is activated by RANKL produced by MRCs; c Medullary LN LECs express CD209 to retain neutrophils, which may be important in clearing lymph-borne pathogens. cLEC ceiling lymphatic endothelial cell, fLEC floor lymphatic endothelial cell, LN lymph node, LEC lymphatic endothelial cell, CCL21 chemokine (C-C motif) ligand 21, CCRL1 chemokine (C-C motif) receptor like 1, CSF1 colony-stimulating factor 1, RANK receptor activator of nuclear factor-kappaB, RANKL receptor activator of nuclear factor-kappaB ligand, DCs dendritic cells, S1P sphingosine 1 phosphate, SCS subcapsular sinus, SSM subcapsular sinus macrophage, MM medullary macrophage, MRC marginal reticular cell. Created with Adobe Illustrator

Lymphatic vessels in central nervous system immunity

Recent studies of meningeal lymphatic vessels revealed an intersection between the immune system and central nervous system.125 Meningeal lymphatic vessels may provide a route for central nervous system-derived immune cell and antigen delivery to cervical lymph nodes and thus prevent central nervous system from infection or injury. Meningeal lymphangiogenesis plays an active role in immune surveillance to protect the central nervous system. In the context of glioblastoma, VEGFC-induced meningeal lymphangiogenesis recruited CD8+ T cells into the tumor and induced a long-lasting antitumor memory response.126 In response to spinal cord injury, VEGFC/VEGFR3 signaling activation-mediated spinal lymphangiogenesis enhanced the immune response by increasing the T cell infiltration rate.127 However, studies have shown that meningeal lymphatic vessels potentially promote pathological processes under autoimmune neuroinflammatory conditions. In the multiple sclerosis context, blocking meningeal lymphatic vessels reduced disease severity and alleviated the inflammatory response, likely by interfering with the trafficking and activation of CCR7+ T cells in draining lymph nodes.128

Lymphatic vessels in gut immunity

Intestinal lymphatic vessels are important components of the gut immunosurveillance system, which promotes the mucosal immune response and tolerance. Intestinal dendritic cells present antigens in response to LEC-derived CCL21 production, which is essential for the establishment of oral tolerance.129 Intestinal dendritic cells also drive the apoptosis of intestinal epithelial cells in mesenteric lymph nodes by transmitting critical signals that induce Treg cell activation.129,130 In addition, different parts of the intestine drain to distinct mesenteric lymph nodes that are immunologically specific to the functional gut segment that they drain. Proximal small intestine-draining mesenteric lymph nodes induce tolerogenic responses, while distal mesenteric lymph nodes induce proinflammatory T cell responses.131

The capillary lymphatics in the intestine (also known as lacteals) function as a secondary barrier defending against potential bacterial infections while simultaneously serving as the primary conduit for the dissemination of pathogens, pathogen-derived toxins, and subsequently tissue-derived proinflammatory mediators. DLL4-specific deletion led to lacteal regression and weakened the local immune response, leading to susceptibility to infection and impaired dietary fat uptake.111 Additionally, lymphatic drainage can influence the composition of the gut microbiota, with increased drainage potentially promoting a healthier microbiota profile and reducing the incidence of colitis. In contrast, reduced drainage may impede pathogen dissemination and reduce proinflammatory factor levels.

Abnormal lymphangiogenesis in human diseases

In the above sections, we provided a detailed account of lymphatic vessels in physiological conditions, encompassing lymphatic vessel development and physiological functions. Furthermore, lymphatic vessels actively participate in pathological processes in human diseases. As the comprehension of lymphangiogenesis in diseases improves, the underlying molecular mechanisms have been elucidating. In this section, we provide a comprehensive elucidation of the pivotal roles of lymphangiogenesis in various prevalent diseases and associated regulatory signaling pathways. Meanwhile, lymphangiogenesis in other diseases is concisely presented in Table 3.Table 3 Lymphangiogenesis in other diseases

Disease	Effect of lymphangiogenesis	Molecular mechanisms and regulatory signaling pathways	Reference	
Chronic obstructive pulmonary disease	1. Lymphangiogenesis is beneficial in reducing lymphedema and airflow obstruction.

2. Lymphangiogenesis increases immune cell trafficking in patients with advanced chronic obstructive pulmonary disease.

	1. Inflammatory cells and epithelial cells promote lymphangiogenesis through the regulation of VEGFC and VEGFD.

2. The expression of CCL21 and chemokine scavenger receptor D6 in LECs of perialveolar lymphatic vessels is increased, which promotes the delivery of immune cells.

	464,465	
Asthma	Impaired lymphangiogenesis disrupts antigen clearance from the lungs and airways.	IL-13 and IL-4 secreted by Th2 cells are identified as potent inhibitors of lymphangiogenesis via JAK/STAT pathways, resulting in the downregulation of PROX1 expression.	466	
Tuberculosis	1. Lymphangiogenesis induced by Mycobacterium tuberculosis granulomas promotes a systemic T cell response against Mycobacterium tuberculosis antigens.

2. LEC in lymph node provides with the natural niche for Mycobacterium tuberculosis replication.

	1. Mycobacterium tuberculosis granulomas promote lymphangiogenesis through the VEGFC/VEGFR3 pathway.

2. Replication of Mycobacterium tuberculosis in the cytoplasmic and phagosome of LECs is dependent on the presence of RD1(encoding ESX-1).

	467,468	
Idiopathic pulmonary fibrosis	1. Perialveolar lymphangiogenesis is positively correlated with the degree of pulmonary fibrosis.

2. Abnormal mural cell coverage of pulmonary lymphatic vessels and impaired lymphatic drainage lead to pulmonary fibrosis.

	1. Increased hyaluronic acid and macrophage transdifferentiation promote alveolar lymphangiogenesis.

2. The recruitment of mural cells is facilitated by LECs through the PDGFβ/PDGFRβ pathway, resulting in compromised lymphatic drainage and promoting fibroblast aggregation, ultimately leading to the development of pulmonary fibrosis.

	469,470	
Heart failure	Endogenous cardiac lymphangiogenesis limits cardiac inflammation and perivascular fibrosis, delaying heart faliure development.	Activation of the VEGFC/VEGFR3 signaling prevents the progression to heart failure.	471,472	
Atherosclerosis	1.Lymphangiogenesis dampens the local inflammatory response at an early stage of plaque development.

2.Disrupted arterial lymphangiogenesis impairs cholesterol efflux from atherosclerotic arteries.

	1.Plaque-associated lymphangiogenesis is partly drove by CXCL12/CXCR4 axis.

2.Increased level of RSPO2 binding to LGR4 in atherosclerotic arteries inhibits lymphangiogenesis through impairment of VEGFC-induced AKT/eNOS/NO signaling.

	117,473	
Myocardial infarction	1.Lymphagiogenesis contributes to the fibrosis maturation and scar formation by eliminating excess protein and fluid in granulation and scar phase.

2.Lymphangiogenesis improves cardiac function and suppresses cardiac edema.

3.Lymphoangiocrine signal produced by LECs is cardioprotective, which contributes to reduced cardiomyocytes death and a smaller scarred myocardial area.4.Lymphangiogenesis prompts LEC penetration into the infarcted myocardium, and activated LECs function as intramyocardial immune hubs promote the formation of immunosuppressive microenvironment, facilitating post-myocardial infarction repair.

	1.VEGFC expressed by cardiomyocytes induces lymphagiogenesis in/around the infarcted lesion.

2.Epicardial-secreted factor Adrenomedullin drives reparative cardiac lymphangiogenesis and function via CX43.

3.LECs-secreted Reelin regulates cardiomyocytes proliferation and survival through the Integrinβ1 signaling pathway.

4.TBX1 in LECs drives a bi-functional LEC transcriptional program that not only promotes lymphangiogenesis but also enhances the immunosuppressive function which mediated by the expression of CCL21 and ICAM1.

	285,474–476	
Non-alcoholic fatty liver disease	1.Disrupt lymphangiogenesis impedes lymphatic vessel stability and liver homeostasis by regulating fibrosis development and immune cell infiltration.

2. Decreased lymphatic permeability disrupts protein homeostasis and increases inflammation, which is based on impeded LEC metabolism and reorganized cell-cell junctions.

	1.OxLDL stimulates the expression of IL-13, thereby inhibiting lymphangiogenesis and affecting lymphatic vessel stability.

2.OxLDL downregulates PROX1, LYVE1, PDPN, and VEGFR3 expression in LECs, which impacts lymphangiogenesis and lymphatic permeability.

	477,478	
Cirrhotic liver	Hepatic lymphangiogenesis promoted by sympathetic nerves prevents liver from portal tract fibrosis.	VEGFC expressed by Schwann cells of sympathetic nerves promotes hepatic lymphangiogenesis.	479	
Endometriosis	Lymphangiogenesis promotes the infiltration of immune cells, aggravating local chronic inflammation and endometriosis development.	1.IL-1β and TNF-α modulate the overexpression of VEGFC via suppressing COUP-TFII in endometriotic stromal cells, which promotes lymphangiogenesis.

2.Upregulated BST2 regulates the transcription of VEGFC via the activation of NF-κB signaling pathway in endometriotic stromal cells, which promotes lymphangiogenesis.

	480,481	
Arthritis	1.Lymphangiogenesis compensatorily improves joint inflammation during chronic arthritis.

2.Induced lymphangiogenesis improves synovial lymphatic drainage and alleviates arthritis damage in age-related osteoarthritis.

	1.Circulating CD11b+ myeloid cells infiltrate in joint inflammation, which produce VEGFC to stimulate lymphangiogenesis.

2.Activation of VEGFC/VEGFR3 signaling pathway stimulates synovial lymphangiogenesis.

	482,483	
VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor, LEC lymphatic endothelial cell, IL interleukin, CCL C-C motif chemokine ligand, Th2 T-helper type 2, RD1 region of difference 1, ESX-1 type VII secretion system, PDGF platelet-derived growth factor, CXCL C-X-C chemokine ligand, RSPO2 R-spondin 2, LGR4 leucine-rich repeat-containing G protein-coupled receptor 4, CX43 connexin 43, TBX1 T-box 1, ICAM1 intercellular adhesion molecule 1, OxLDL oxidized low-density lipoprotein, PROX1 prospero homeobox 1, LYVE1 lymphatic vessel endothelial receptor 1, PDPN podoplanin, TNF necrosis factor, COUP-TFII chicken ovalbumin upstream promoter-transcription factor II, BST2 bone marrow stromal antigen 2, NF-κB nuclear factor-kappa B

Lymphedema and lymphatic malformation

Lymphedema

Lymphedema is a chronic, progressive accumulation of protein-rich fluid in the interstitium due to lymphatic vessel deficiency, resulting in inflammation, fat deposition, and fibrosis. Lymphedema is classified into primary disease caused by congenital abnormalities or secondary disease caused by the injury of iatrogenesis, trauma, and infection. Primary lymphedema, a rare inherited autosomal dominant disorder, is initially characterized by mutations in FLT4 (which encodes VEGFR3). Germline mutations responsible for primary lymphedema have been identified in 28 genes that encode proteins mainly involved in VEGFR3 signaling and these encoded proteins include transcription factors such as GATA2, FOXC2, and SOX18. The majority of mutations result in reduced activation of the VEGFR3 pathway.110 Secondary lymphedema arises as a result of infection, trauma or surgery.132 Current treatment strategies include mainly physical or surgical interventions to alleviate edema and these treatments include decongestive therapy, intermittent pneumatic compression and liposuction.133 In addition, recent studies have revealed the efficacy of pharmacotherapy and cell-based therapies in the treatment of lymphedema.134,135

Lymphatic malformation

Lymphatic malformation is a benign congenital vascular disease characterized by abnormal lymphatic vessel development. It is caused by single somatic mutations, most of which are in genes encoding components of oncogenic growth factor-activated signal transduction pathways.136 The classification of lymphatic malformations is based primarily on clinical manifestations. Cystic lymphatic malformation is the most prevalent type of congenital lymphatic malformation, presenting as solitary lesions of variable sizes. Based on appearance, it is classified into macrocystic, microcystic, or mixed cystic lymphatic malformation.136 Most cystic lymphatic malformations are caused by a causative mutation in PIK3CA. Most PIK3CA mutations causing cystic lymphatic malformation activate the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling cascade.137 Complex lymphatic malformations are characterized as multifocal lesions or defection occurring in central collecting lymphatic vessels and show overlapping and variable clinical features. These features include generalized lymphatic anomaly, Gorham-Stout disease, Kaposiform lymphangiomatosis, and central conducting lymphatic anomaly.138 Similar to the cause of cystic lymphatic malformation, a causative somatic PIK3CA mutation (His1047Arg) has been reported in generalized lymphatic anomaly.139 In other types of complex lymphatic malformations, mutations in genes encoding components of the RAS/MAPK pathway have been reported, including mutations in NRAS and ARAF.140,141 Furthermore, germline heterozygous kinase-dead mutations in the gene encoding EPHB4 could activate MAPK signaling in cases of central conducting lymphatic anomaly.142 The choice of therapy is based on the location and size of the malformation, and the affected tissues. Pharmacotherapy, surgical resection, sclerotherapy, and thermal ablation can be used to control and relieve symptoms of recurrent effusions, infection, and pain in lymphatic malformations.136

Lymphangiogenesis in cancer

In the past, cancer-associated lymphatic vessels were considered passive transporters of cancer cells. However, recent studies revealed that lymphatic vessels actively participate in the process of cancer metastasis through their dynamic changes, mostly mediated via lymphangiogenesis. Lymphangiogenesis requires the coordination of complex cellular events, including proliferation, sprouting, migration, and tube formation.46 Tumor-associated lymphangiogenesis, with its resultant increased permeability and enlargement of lymphatic vessels, synergistically promotes cancer metastasis.143 Depending on the type and site of a tumor, the signaling pathways for lymphangiogenesis vary. Moreover, targeting lymphangiogenesis to inhibit cancer metastasis has been proven to be a valuable therapeutic strategy. In this section, we summarize the abnormal lymphangiogenesis in various cancers (Figs. 11, 12).Fig. 11 Lymphangiogenesis in cancers. Lymphangiogenesis plays a crucial role in lymph node metastasis, which is associated with poor prognosis and overall survival in a range of malignancies. The molecular mechanisms underlying lymphangiogenesis exhibit diversity across different cancer contexts, potentially suggesting targeted therapeutic strategies for cancers. Created with BioRender.com

Fig. 12 Lymphangiogenesis and lymph node metastasis in cancer. a Lymphatic vessels undergo sprouting, filopodia formation, and lymphatic vessel enlargement; b The disruption of lymphatic vessels and augmented permeability contribute to the intravasation of cancer cells into lymphatic vessels; c An increased coverage by LSMCs and a higher innervation present in the dilated collecting lymphatic vessels, which coordinately enhances collecting lymphatic vessel contractility and pumping frequency; d LECs forming the boundaries of the SCS create and maintain chemokine gradients that direct cancer cells to arrive in the SCS of MLN. Furthermore, LECs within the MLN upregulate adhesion molecules, that further support cancer cell colonization. LV lymphatic vessel, LSMC lymphatic smooth muscle cell, LEC lymphatic endothelial cell, SCS subcapsular sinus, MLN metastatic lymph node. Created with BioRender.com

Nervous system cancer

Glioma

Malignant glioma is the most common primary cancer of the central nervous system. The expression levels of lymphangiogenic factors (PDPN, VEGFC/D, VEGFR3) are increased in high-grade gliomas, with their expression significantly higher at relapse than it was in the primary tumor.144 In addition, microenvironmental stress, including hyperthermia and oxidative stress, has been reported to enhance LEDGF activity, which increases the transcription and expression of VEGFC, thereby promoting lymphangiogenesis.145 However, Hu et al. found that meningeal lymphangiogenesis mediated by VEGFC enhanced the efficacy of anti-PD-1/CTLA-4 combination therapy, which was abolished by CCL21/CCR7 blockage.146

Neuroblastoma

Neuroblastoma is one of the most common cancers in children. Lymphangiogenesis in neuroblastoma is associated with upregulated VEGFC, VEGFD, and VEGFR3, which promotes lymph node metastasis and leads to poor prognosis.147 Endogenous soluble VEGFR2 inhibits the activation of VEGFR3 by binding to VEGFC, thereby inhibiting LEC proliferation. In the context of advanced neuroblastoma, the downregulation of sVEGFR2 is correlated with the disease progression.148 Furthermore, an anti-VEGFD monoclonal antibody, cVE199, specifically binds VEGFD to inhibit the binding of VEGFD to VEGFR3, thereby significantly reducing the lymphangiogenesis in the context of primary lesions.149

Thoracic cancer

Non-small cell lung cancer

The presence of lymphangiogenesis promoting lymph node metastasis is a crucial determinant for unfavorable prognosis in patients with non-small cell lung cancer. Lymphangiogenesis, indicated by an elevated density of PDPN-positive peritumoral lymphatic vessels, has been demonstrated to be associated with cancer progression and unfavorable prognosis in patients with non-small cell lung cancer.150 Watari et al. found that highly metastatic human lung cancer cells have the capability to secrete IL-1, which induces the M2-type polarization of macrophages, augmenting VEGFC expression and subsequently increasing the lymphangiogenesis.151 In addition, the overexpression of ITGA6 enhanced the tube formation capacity of LECs, thereby promoting lymphangiogenesis and accelerating subsequent lymph node metastasis in the lung adenocarcinoma context.152 Moreover, estrogens in females promoted lymphangiogenesis through an estrogen receptor alpha-dependent pathway in Lewis lung cancer.153 Additionally, Hu’s team found that miR-128, functioning as a cancer suppressor, directly targeted VEGFC and subsequently inhibited extracellular signal-regulated kinase (ERK), AKT, and p38 signaling pathway activation to impede lymphangiogenesis in the non-small cell lung cancer context.154

Breast cancer

The dissemination of breast cancer cells is primarily mediated through lymphatic vessels. Increased lymphatic vessel density has been associated with lymph node metastasis and poorer survival in patients with breast cancer.155 The interaction between PDPN and LEC-derived galectin-8 contributed to the activation of promigratory integrin β1, thereby augmenting PDPN-expressing macrophages proximal to lymphatics, which subsequently stimulated local matrix remodeling and promoted lymphangiogenesis.156 Weichand et al. revealed that S1PR1 on tumor-associated macrophages promoted lymphangiogenesis and metastasis via NLRP3/IL-1β.157 In addition, Zheng et al. found that the hypomethylation of the long noncoding RNA (lncRNA) HUMT promoted lymphangiogenesis and metastasis by enhancing FOXK1 transcription to activated the AKT/mTOR and VEGFC signaling pathways in breast cancer cells.158 A recent study conducted by Li et al. revealed that the transcription factor ZKSCAN5 directly interacted with SETD7, forming a complex at the VEGFC promoter. This interaction effectively regulated the expression of VEGFC, inducing tube formation of LECs and promoting lymphangiogenesis.159 Furthermore, NADPH oxidase 4 promoted lymphangiogenesis via the ROS/ERK/CCL21 signaling pathway and providing the entry for metastasis of CCR7-expressing breast cancer cells.160 Nectin-4 induced chemotactic interactions between CXCR4-expressing cancer cells and CXCL12-expressing LECs, which stimulated VEGFC and LYVE1 expression to promote LEC proliferation and migration, ultimately promoting lymphangiogenesis.161 Additionally, heat shock protein 90α significantly enhanced the migration and tube formation abilities of LECs to promote lymphangiogenesis via the LRP1/AKT/CXCL8 signaling pathway.162 Chemotherapy remains an effective treatment for breast cancer, although its efficacy may be influenced by lymphangiogenesis. Harris and colleagues found that lymphangiogenesis induced by platinum chemotherapy increased the rate of lymph node metastasis in breast cancer, which was prevented by adjuvant anti-VEGFR3 therapy.163

Digestive system cancer

Hepatocellular cancer

Hepatocellular cancer is the most common type of liver cancer.164 High lymphatic vessel density has been associated with reduced survival and disease-free survival of patients with hepatocellular cancer.165 VEGFD-overexpressing hepatocellular carcinoma cells promote lymphangiogenesis, resulting in an increased rate of lymph node metastasis.166 Furthermore, lncRNA HANR, which regulates exosomal miR-296 secretion, may induce lymphangiogenesis via the EAG1/VEGFA axis in LECs.167 Targeting lymphangiogenesis has been proposed as a promising approach for suppressing hepatocellular cancer metastasis. An IgG-like fusion protein molecule (VEGF receptor 31-immunoglobulin, VEGFR31-Ig) binding VEGFC has been developed to inhibit lymphangiogenesis, thereby suppressing cancer growth and metastasis.168

Intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma is an aggressive and lethal type of primary liver cancer.169 Lymphangiogenesis has been correlated with an increased risk of lymph node metastasis and reduced overall survival in patients with intrahepatic cholangiocarcinoma.170 Carpino et al. found that THB1, THBS2, and PEDF released into the intrahepatic cholangiocarcinoma stroma induced lymphangiogenesis, which contributed to preferential lymph node metastasis of intrahepatic cholangiocarcinoma.171 Furthermore, cholangiocarcinoma-derived PDGFD activated LEC-adjacent fibroblasts, which secreted VEGFC and VEGFA, resulting in lymphangiogenesis to promote cancer cell intravasation.172 Moreover, PDGF-BB secreted by cancer-associated fibroblasts activated the receptor PDGFR-β and downstream ERK1/2-JNK signaling pathways in LECs to promote lymphangiogenesis.173

Pancreatic cancer

The high lethality of pancreatic cancer stems from its propensity for rapid dissemination in the lymphatic system and distant organs, and lymph node metastasis may occur early in the course of pancreatic cancer development.174 Similar to its effect on other cancer types, VEGFC may mediate lymphangiogenesis in the context of pancreatic cancer. Under hypoxic conditions, BANCR is overexpressed in pancreatic cancer and promotes lymphangiogenesis by upregulating the HIF-1α/VEGFC/VEGFR3 pathway.175 In contrast, circular RNA (circRNA) circNFIB1 exerts a suppressive effect on lymphangiogenesis by downregulating the effect of miR-486-5p and upregulating PIK3R1 expression to inhibit VEGFC signaling.176 VEGFC could be secreted from cells in extracellular vesicles to facilitate lymphangiogenesis. Wang et al. reported that the downregulation of DUSP2 in pancreatic cancer enhanced extracellular vesicle-associated secretion of VEGFC. Thus, VEGFC enhances lymphangiogenesis and cancer cell invasion into lymphatic vessels through paracrine and autocrine mechanisms, ultimately leading to lymph node metastasis.177 Additionally, based on the aforementioned mechanism, Wang et al. reported a selective inhibitor B390 of HDAC1/2 that effectively suppressed lymphangiogenesis by reinstating DUSP2 expression.178 Other studies have been aimed at understanding lymphangiogenesis independent of VEGFC action. KRAS(G12D)-mutated pancreatic cancer cells maintained the secretion of extracellular vesicles carrying hnRNPA1 in a SUMOylation-dependent manner, thereby promoting lymphangiogenesis through the stabilization of PROX1 mRNA in vesicle-recipient LECs.179 Furthermore, Zhou et al. demonstrated that exosomes derived from pancreatic cancer cells exerted a stimulating effect on the proliferation and migration of LECs via the downregulating ABHD11-AS1 expression, to promote lymphangiogenesis.180 With the recent development of the “medicine-industry combination”, Shen et al. utilized three-dimensional imaging technology to observe the relationship between primary pancreatic cancer and lymphatic vessel networks, revealing peritumoral lymphangiogenesis, laying a technological and morphological foundation for future systematic detection and three-dimensional analysis of lymphatic invasion in tumor microenvironment (TME).181

Gastric cancer

Lymph node metastasis represents the predominant pattern of gastric cancer dissemination, with lymphangiogenesis emerging as a pivotal contributing factor. The evidence suggests that gastric cancer cells stimulate lymphangiogenesis through the secretion of VEGFC, a process typically facilitated by other regulatory factors, such as transforming growth factor β1 (TGFβ1) and MACC1, in the TME.182,183 Our recent study reported that CRIP1 reshaped the gastric TME to increase the lymphangiogenesis and lymphatic vessel permeability by increasing the amount of secreted VEGFC and CCL5.184 Additionally, tumor-associated lymphangiogenesis and lymph node metastasis is influenced by metabolic factors. Yang et al. demonstrated that the elevation of oxLDL levels in plasma induced the activation of the nuclear factor (NF)-κB pathway through binding with LOX-1, leading to the upregulation of VEGFC expression and subsequently facilitating lymphangiogenesis.185 The rate-limiting enzyme SOAT1 in the cholesterol metabolic pathway exerts effect by upregulating the SREBP1 and SREBP2 expression.186 Furthermore, recent studies have also reported several factors that impede lymphangiogenesis in gastric cancer. Among them, kallistatin exerts its inhibitory effects on lymphangiogenesis and lymphatic node metastasis by downregulating the expression and secretion of VEGFC through the LRP6/IKK/IκB/NF-κB pathway.187 Furthermore, some compounds, such as auramycin G and Babao Dan, exert inhibitory effects on lymphangiogenesis through the downregulation of VEGFC, and curcumin hinders lymphangiogenesis by targeting the HMGB1/VEGFD axis.188–190

Colorectal cancer

Colorectal cancer, a prevalent gastrointestinal malignancy, frequently progresses to lymph node metastasis. Lymphangiogenesis indicates a higher risk of local recurrence and poorer prognosis in patients with colorectal cancer.191 Metastasis-associated protein 1 has been demonstrated to induce VEGFC expression and promote lymphangiogenesis in colorectal cancer.192 Moreover, Xiang’s team found that colorectal cancer-derived exosomes promoted lymphangiogenesis in sentinel lymph nodes through IRF-2, which induced VEGFC expression in macrophages.193 CCBE1, expressed and secreted by colorectal cancer cells and cancer-associated fibroblasts, facilitated lymphangiogenesis through the promotion of VEGFC proteolysis and maturation, while its activity was negatively regulated by TGFβ signaling.194 The development of therapeutic approaches targeting lymphangiogenesis for the treatment of colorectal cancer is currently ongoing. Qingjie Fuzheng Granule and Pien Tze Huang exhibit inhibitory effects on tumor growth and lymphangiogenesis via the PI3K/AKT/VEGFC pathway.195,196 In addition, an ethanol extract of Hedyotis diffusa Willd suppresses VEGFC-stimulated LEC migration and tube formation while concurrently downregulating the expression of downstream molecules involved in the VEGFC/VEGFR3 signaling pathway, such as MMP2, MMP9, cyclin D1, and CDK4.197

Genitourinary cancer

Bladder cancer

Bladder cancer is a highly prevalent malignancy in the genitourinary system.164 Higher lymph vessel density has been correlated with decreased metastasis-free survival of patients with bladder cancer.198 Changhao Chen and colleagues found that the lncRNA LINC01296, termed LNMAT1, epigenetically induced CCL2 expression in bladder cancer cells, recruiting macrophages to the TME, which induced lymphangiogenesis via VEGFC secretion.199 Afterward, the team identified another lncRNA known as LNMAT2 in exosomes secreted by bladder cancer cells that stimulated LEC tube formation and migration via epigenetically acting on the PROX1 promoter to upregulate the expression.200 Subsequently, Chen et al. discovered that EV-mediated ELNAT1 also promoted lymphangiogenesis via the transcriptional upregulation of SOX18 expression in human LECs via SUMOylation motification.201 In addition, overexpression of the lncRNA BLACAT2 stimulated lymphangiogenesis by binding WDR5, the core subunit of human H3K4 methyltransferase complexes, to increase the expression of VEGFC.202 The novel circRNA circEHBP1 mediated TGFβR1 overexpression and activated the TGFβ/SMAD3 signaling pathway in bladder cancer cells, thereby promoting the secretion of VEGFD to drive lymphangiogenesis.203 The inhibition of lymphangiogenesis is a promising therapeutic strategy for impeding lymph node metastasis in patients with bladder cancer. Blocking the VEGFC/D signaling pathways by administering soluble VEGFR3 encoded by adenovirus or using clodronate liposomes for depletion of tumor-associated macrophages may markedly inhibit lymphangiogenesis in patients with bladder cancer.204

Prostate cancer

The incidence of prostate cancer is highest among all the malignancies affecting the male reproductive system. Previous studies have demonstrated that elevated lymphatic vessel density in conjunction with increased VEGFC expression was indicative of metastasis and unfavorable prognosis in patients diagnosed with prostate cancer.205 Lysophosphatidic acid increased the expression of VEGFC and promoted lymphangiogenesis by upregulating calreticulin in prostate cancer cells.206 Relevant studies are currently ongoing to investigate the potential of targeted lymphangiogenesis therapy in managing lymph node metastasis and distant metastasis of prostate cancer. The administration of a VEGFC ligand trap (soluble VEGFR3) or anti-VEGFR3 antibody (mF4-31C1) resulted in a significant reduction in the lymphangiogenesis, as well as metastasis to regional lymph nodes and distant organs.207 Yano et al. revealed that glucocorticoids suppressed lymphangiogenesis by downregulating the expression of VEGFC.208

Ovarian cancer

Ovarian cancer is one of the most aggressive gynecological cancers and is associated with poor prognosis. High lymphatic vessel density has been found to be significantly associated with lymph node metastasis and recurrence in patients with ovarian cancer.209 Sapoznik et al. found that follicle-stimulating hormone enhanced the interaction between LEDGF and the VEGFC promoter, thereby increasing VEGFC expression and promoting lymphangiogenesis.210 Additionally, the overexpression of Her-2/NEU increased the endothelial permeability and facilitated lymph node metastasis by upregulating the expression of VEGFC.211 Cheng and his colleagues found that hypoxia-induced secretion of HIF-1α facilitated lymphangiogenesis and expedited metastasis through the ALKBH5/m6A-ITGB1/FAK signaling pathway.212 Other factors modulate lymphangiogenesis to influence the rate of lymph node metastasis in ovarian cancer. For example, SPARC, a Ca2+-binding matricellular glycoprotein, has been demonstrated to inhibit lymphangiogenesis by downregulating VEGFC and VEGFD expression.213

Cervical cancer

Patients with cervical cancer and lymph node metastasis face a dismal prognosis, and lymphangiogenesis promotes the dissemination of cervical cancer cells to regional lymph nodes. Chen et al. found that TNFα promoted lymphangiogenesis by VEGFC-mediated activation of the AKT and ERK pathways, which was suppressed by MAZ51, a VEGFR3 inhibitor.214 PTPRM, which has been identified as an independent prognostic factor of patients with cervical cancer, can induce VEGFC-dependent lymphangiogenesis.215 Upregulated expression of FASN and FABP5, which both play important roles in lipid metabolism, has been positively correlated with the lymph node metastasis of cervical cancer.216,217 As a pivotal enzyme in lipid metabolism, FASN stimulated the secretion of PDGF-AA and IGFBP3 by cervical cancer cells, thereby facilitating lymphangiogenesis and promoting metastasis.216 Furthermore, the upregulation of FABP5 reprogrammed fatty acid metabolism, leading to an increase in intracellular fatty acids that activated the NF-κB pathway, resulting in lymphangiogenesis in cervical cancer.217 Additionally, exosomal miR-221-3p secreted by cervical cancer cells was transferred to LECs, thereby activating the ERK and AKT pathways through downregulation of VASH1 and promoting lymphangiogenesis.218 A recent study reported that circVPRBP interacted with RACK1 and shielded the S122 O-GlcNAcylation site, thereby inducing RACK1 degradation, which subsequently suppressed galectin 1-mediated lymphangiogenesis and lymph node metastasis in cervical cancer.219

Papillary thyroid cancer

Lymphangiogenesis has been demonstrated to facilitate lymph node metastasis in papillary thyroid cancer. Choi et al. found that increased lymphatic vessel density, as assessed by high PDPN and VEGFR3 expression, was significantly associated with the incidence of lymph node metastasis in the papillary thyroid cancer context.220 Additionally, recurrent papillary thyroid cancer exhibited higher peritumoral lymphatic vessel density than nonrecurrent thyroid cancer.221 Moreover, lncRNA MFSD4A-AS1 functioned as a competing endogenous RNA to disrupt miRNA-mediated VEGFA/C repression and activated TGFβ signaling, thereby promoting lymphangiogenesis.222

Melanoma

Melanoma is an extremely malignant cutaneous cancer with a high propensity for metastasis, predominantly through lymph node metastasis. The prognostic significance of lymphatic vessel density in melanoma has been documented, with higher densities associated with a poorer prognosis.223 Melanoma-derived melanosomes facilitate the transfer of let-7i to LECs, thereby triggering type I IFN signaling and promoting lymphangiogenesis.224 Moreover, melanoma cells secrete extracellular vesicles enriched with NGFR, which promotes lymphangiogenesis and facilitate cancer cell adhesion through the induction of ERK kinase activity, activation of NF-κB, and upregulation of ICAM-1 expression in LECs.225 The high expression of CD147 within melanoma cells has been reported to stimulate lymphangiogenesis through the upregulation of PROX1 expression.226 Additionally, both Adrenomedullin and Apelin have been demonstrated to enhance lymphangiogenesis in melanoma.227,228 In the context of melanoma, claudin-3 exerted an inhibitory effect on lymphangiogenesis through the downregulation of VEGFC and PI3K signaling pathways.229 Additionally, various inhibitors targeting lymphangiogenesis have been documented, including rapamycin and a novel 2-aminobenzimidazole derivative called MFB, which effectively suppressed lymphangiogenesis by downregulating VEGFs.230,231 Interestingly, Sasso et al. demonstrated that the induction of lymphangiogenesis through VEGFC increased the efficacy of immunotherapy, thereby presenting a novel therapeutic strategy for cancer treatment targeting lymphangiogenesis.232

Alzheimer’s disease

Alzheimer’s disease is the most common form of dementia, in which impaired amyloid-β clearance from the brain is the core etiology.233 Meningeal lymphatics are involved in the clearance of molecules, including amyloid-β (as explained in “Lymph absorption and transport in meningeal lymphatic vessels”), and their dysfunction is an aggravating factor in Alzheimer’s disease pathology.234 Modulation of lymphatic vessel function might be a novel therapeutic strategy for Alzheimer’s disease. Recent studies have shown that VEGFC treatment promoted meningeal lymphangiogenesis in transgenic mice, which decreased the level of soluble amyloid-β in cerebrospinal fluid.234,235 Moreover, the therapeutic delivery of VEGFC enhanced meningeal lymphatic function to increase the clearance rate of amyloid-β by monoclonal antibodies.236

Ocular hypertension and glaucoma

Glaucoma is the foremost cause of irreversible blindness, with elevated intraocular pressure being the most crucial risk factor. Ocular lymphatic vessels and Schlemm’s canal play pivotal roles in regulating intraocular pressure under the physiological condition (as outlined in “Lymph absorption and transport in ocular lymphatic vessels”). VEGFC/VEGFR3 plays a crucial role in the development and maintenance of Schlemm’s canal. The application of recombinant VEGFC resulted in the promotion of Schlemm’s canal growth in mice and led to a tendency toward decreased intraocular pressure.237 Kim et al. found that Schlemm’s canal integrity was maintained via the interconnected and coordinated functions of ANG/TIE2 signaling, aqueous humor outflow and PROX1 activity. Deletion of ANG1/ANG2 or TIE2 severely impaired the integrity of Schlemm’s canal, resulting in elevated intraocular pressure, retinal neuron damage, and impaired retinal ganglion cell function, all hallmarks of primary open-angle glaucoma.238 Recently, SVEP1 was identified as a modifier of TEK expression during Schlemm’s canal development and affected the penetrance and severity of primary congenital glaucoma disease.239 However, the underlying mechanism through which ocular lymphatic dysfunction contributes to the pathogenesis of glaucoma remains unclear, and further investigations are needed to gain a comprehensive understanding.

Obesity and lipedema

Obesity is characterized by excessive adipose tissue accumulation resulting from an imbalance between energy intake and expenditure.240 Adipose tissue is no longer considered solely an energy storage depot but has been recognized as an active endocrine organ that secretes numerous adipokines and proinflammatory cytokines.241 Obesity is widely acknowledged to be a significant clinical risk factor for the development of lymphedema. Obesity-induced chronic inflammation, fibrosis, and increased adipose tissue deposition detrimentally impact lymphatic vessel function, thereby exacerbating the inflammatory response and precipitating the development of lymphedema.242 A decrease in lymphatic vessel density has also been observed in murine models of obesity.243 Therefore, maintaining a normal number and function of lymphatic vessels may potentially ameliorate the metabolic disruption in obese patients. The study conducted by Chakraborty et al. substantiated this possibility, demonstrating that an increased VEGFD-induced lymphangiogenesis in adipose tissue mitigated the obesity-related immune accumulation and increased the metabolism.244 Subsequently, they observed that VEGFD-induced lymphangiogenesis in adipose tissue resulted in a decrease in the macrophage populations and accelerated systemic fatty acid utilization, thereby facilitating the remodeling of the inflammatory response.245

Lipedema, often misidentified as lymphedema or obesity, is a chronic progressive disease characterized by disproportional adipose tissue distribution and limb pain, predominantly in women. Patients with lipedema present with features of lymphedema, particularly in advanced stages, which may arise from the synergistic effects of lymphatic abnormalities and lipid accumulation. Amann et al. employed fluorescence microlymphography and thus identified beadlike dilated lymphatic vessels in individuals with lipedema.246 In addition, Lohrmann et al. revealed functional and morphological aberrations in the lymphatic vessels of lower extremities in lipedema patients.247 In terms of lymphatic abnormalities as potential etiologies for lipedema, the leakage of lymph fluid has been shown to promote adipocyte proliferation significantly.248 However, imbalanced and prolonged adipose tissue expansion may contribute to abnormal contraction of collecting lymphatic vessels, as observed by Blum et al. in mice chronically fed a high-fat diet.249 Expanded adipocytes secreted certain lymphangiogenic factors, such as VEGFC, VEGFD and ANG2.250 In light of these findings, further investigations are warranted to elucidate the intricate association between lipedema and lymphatic vessel impairment.

Diabetes mellitus

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia and abnormal carbohydrate, fat, and protein metabolism.251 Impaired lymphangiogenesis is a complication of diabetes mellitus. Wenstedt et al. observed that salt-sensitive increases in blood pressure in individuals with Type 1 diabetes may be linked to the absence of macrophages and thus reduced lymphangiogenesis.252 Wu et al. demonstrated that diabetes-induced ROS-activated c-Src-dependent phosphorylation of VEGFR3 and upregulation of epsin expression, causing VEGFR3 degradation via the interaction between epsin and VEGFR3, ultimately leading to impaired lymphangiogenesis.253 In patients with Type 2 diabetes, increased lymphatic permeability has been demonstrated to lead to lymphatic vessel dysfunction. Scallan et al. initially identified increased permeability in the collecting lymphatic vessels in individuals with Type 2 diabetes, leading to lymphatic leakage. This outcome was attributed to the diminished bioavailability of NO, which was rectified by inhibiting the action of the NO-degrading enzyme phosphodiesterase 3.254 Similarly, Cifarelli et al. observed that the downregulation of VEGFC/VEGFR2/AKT after CD36 silencing resulted in VE cadherin degradation and subsequently increased lymphatic vessel permeability in individuals diagnosed with Type 2 diabetes.255 The prolonged hyperglycemia associated with diabetes can cause oxidative stress, advanced glycation end-product formation, and inflammation, which can lead to significant damage to various organs, such as the kidneys and eyes.256 Recent studies have demonstrated the involvement of lymphatic vessels in the pathogenesis of these complications.

Diabetic kidney disease

Hyperglycemia and other metabolic abnormalities in diabetes can lead to ultrastructural and functional changes in the glomeruli and tubules, eventually causing diabetic kidney disease.257 A study by Kim et al. showed that inhibiting lymphangiogenesis alleviated lipid overload induced by diabetic kidney disease and relieved symptoms.258 Mechanistically, this outcome was caused by lymphangiogenesis in diabetic kidney disease, which promoted tubulointerstitial fibrosis in the kidneys.259 Subsequently, Hwang et al. demonstrated that the mitigation of kidney damage in diabetic kidney disease was achievable through targeted inhibition of lymphangiogenesis using a specific VEGFR3 inhibitor.260 Collectively, these studies indicated that targeting lymphangiogenesis-related factors may be a viable therapeutic strategy for diabetic kidney disease.

Diabetic retinopathy

Diabetic retinopathy is a common ocular complication of diabetes that can eventually lead to vision loss.261 Aberrant lymphangiogenesis has been observed to be involved in the pathogenesis of diabetic retinopathy.262,263 Gucciardo et al. observed that the microenvironment of diabetic retinopathy can promote pathological lymphangiogenesis.264 Korhonen et al. identified significant enrichment of genes and signaling pathways associated with lymphatic vessel development in tissues obtained from patients diagnosed with diabetic retinopathy through mRNA sequencing and Gene Ontology and pathway enrichment analyses.265 However, the mechanisms underlying pathological lymphangiogenesis contributions to the pathogenesis of diabetic retinopathy are currently unknown, and further investigation is required.

Diabetic wound healing

Lymphatic dysfunction in diabetes mellitus may lead to the impaired transport of immune cells, growth factors, and other molecules involved in tissue regeneration, resulting in delayed wound healing.266 Several studies have shown that the activation of lymphangiogenesis facilitates diabetic wound healing.267,268 Topical simvastatin or negative-pressure wound therapy are potential therapeutic approaches to promote wound healing in people with diabetes mellitus, and the mechanisms underlying these therapies both involve the promotion of lymphangiogenesis.269–271 In addition, some lncRNAs have also been shown to promote diabetic wound healing by promoting lymphangiogenesis.272,273 Considering these findings, researchers engineered a new tissue material to induce lymphangiogenesis, paving the way for the development of novel strategies to facilitate diabetic wound healing.274

Wound healing

Wound healing is a complex and dynamic process that involves a series of overlapping stages to restore tissue integrity and function. It encompasses revascularization, inflammation, innervation, and remodeling.275 Activation of lymphangiogenesis pathways is considered an effective strategy to facilitate healing of chronic wounds and alleviate tissue inflammation, which is mainly induced by VEGFC/VEGFR3 signaling.276 During the wound healing process, platelets promote the release of VEGFC, thereby facilitating lymphangiogenesis. Immune cells, proteins, and fluids are transported out of the wound area through newly formed lymphatic vessels.277 Stabilized expression of HIF-1α in a wound also promotes the expression of VEGFC, thereby regulating lymphangiogenesis.278 Hosono et al. found increased expression of COX-2 and mPGES-1 at wound sites and showed that these proteins promoted the expression of VEGFC and induced lymphangiogenesis.279 Notably, impaired or insufficient lymphangiogenesis may result in hindered or incomplete wound healing.280

In addition, lymphatic vessels form a specific niche for the regeneration of diverse tissues. Dermal capillary lymphatic vessels regulate the regeneration of hair follicles by dynamically interacting with stem cells. Mechanically, activated hair follicle stem cells express ANG-like protein 4 to promote capillary lymphatic vessel remodeling and reduce lymph drainage to initiate hair follicle regeneration.281,282 Skeletal lymphatic vessels mediate the regeneration of bone and hematopoietic stem cells under genotoxic stress conditions. Biswas et al. recently found that skeletal lymphangiogenesis specifically recruited and enhanced the proliferation of mature Myh11+CXCR4+ pericytes via secreting CXCL12, inducing their differentiation into osteoblasts and contributing to bone regeneration.283 Moreover, they found through experiments that inhibition of skeletal lymphangiogenesis reduced the proportion of hematopoietic stem cells, indicating a particularly potent regenerative function of lymphatic vessels.283 Additionally, lymphatic vessels have been shown to be indispensable for heart regeneration after myocardial infarction. Gancz et al. found that the lack of cardiac lymphatic vessels impaired heart regeneration by preventing VEGFC/VEGFR3 signaling in zebrafish.284 Epicardium-derived Adrenomedullin signaling in mice stimulated regenerative cardiac lymphangiogenesis via lateralization of CX43, which is a potential therapeutic target for cardiac regeneration.285

Transplant rejection

Types of transplant rejection include host-versus-graft disease (HVGD) and graft-versus-host disease (GVHD). HVGD is an immune-mediated response wherein the recipient’s immune system discerns the transplanted organ as an exogenous entity and subsequently initiates an immunological assault against it.286 Lymphatic vessels play crucial roles as conduits for antigen-presenting cells and soluble antigens, thereby facilitating their transport. Surgical intervention resulting in disrupted lymphatic vessel integrity can lead to impaired lymphatic drainage, consequently impacting both acute and chronic rejection responses after transplantation. Moreover, lymphangiogenesis exhibits heterogeneity in transplant rejection among organs.287 During ischemia-reperfusion injury in rat heart allografts, activation of the VEGFC/VEGFR3 axis induced lymphangiogenesis and subsequently exacerbated allograft inflammation.288 After the transplantation of minor antigen sex-mismatched murine heart grafts, an increase in the lymphatic flow index was associated with higher lymphatic vessel density and inflammatory infiltration of T cells and macrophages.289 VEGFR3 is involved in the trafficking of immune cells from peripheral tissues to secondary lymphoid organs by regulating the production of CCL21 in allogeneic lymphatic vessels. Adenovirus VEGFR3-Ig inhibited lymphangiogenesis and attenuated cardiac allograft rejection by reducing the number of transported and activated antigen-presenting cells.290 Additionally, Kerjaschki et al. demonstrated that lymphangiogenesis contributed to nodular mononuclear infiltration while also played a role in sustaining a potentially detrimental alloreactive immune response in hosts after renal transplant.291 Mechanistically, the nodular infiltrates contained a significant number of CCR7-positive immune cells, which appeared to be attracted by SLC/CCL21 produced and released by LECs.291 However, it has been suggested that lymphangiogenesis plays a pivotal role in enhancing the survival of allografts. Hyaluronic acid has been identified to induce inflammation and contribute to the development of chronic allograft rejection.292 Cui et al. found that stimulation of lymphangiogenesis using VEGF-C156S, a mutant form of VEGFC selectively binding to VEGFR3, resulted in the attenuation of an established rejection response and increased the clearance of hyaluronic acid from lung allografts.293 Pedersen et al. found that lymphangiogenesis in a mouse model of renal transplant rejection extended the lifespan of the recipients, which may have been related to immune tolerance promoted by lymphangiogenesis.294

GVHD is an immune response of immunocompetent cells in the graft against histocompatibility antigens in the host, resulting in damage to the host. Acute GVHD is triggered by alloreactive T cells that damage peripheral tissues and lymphoid organs.295 Gehlsen et al. found that lymphangiogenesis is involved in the pathogenesis of ocular GVHD.296 In addition, Mertlitz et al. found that acute GVHD was associated with lymphangiogenesis in murine allo-HSCT models and in intestinal tissue biopsy samples taken from patients, while the administration of anti-VEGFR3 antibodies suppressing lymphangiogenesis ameliorated GVHD and prolonged the survival in murine models.297

Therapeutic interventions and clinical research progress of lymphangiogenesis

Many past and present efforts have been made to study and reveal the interventions of lymphangiogenesis under physiological and pathological conditions. In the following section, we summarize the known promoters and inhibitors of lymphangiogenesis, list therapeutic interventions, and describe the progress in their clinical applications.

Interventions of lymphangiogenesis

VEGFs

Agonistic effects of VEGFs

Among VEGF family members, VEGFC and VEGFD are the best-characterized and specific growth factors for lymphatic vessels. Generally, VEGFC and VEGFD function as ligands that bind receptors on the LEC membrane and then activate downstream signaling cascades to promote lymphangiogenesis. VEGFC and VEGFD both bind to the receptor VEGFR3, which is commonly expressed by LECs.298,299 After binding of VEGFC or VEGFD, VEGFR3 dimerizes and is phosphorylated, leading to the activation of its cytoplasmic tail tyrosine kinase activity. The phosphorylation of VEGFR3 leads to the recruitment of some important proteins, such as GRB2, CRK, and SHC, which mediate the activation of downstream signaling pathways, including the conserved PI3K/AKT, MAPK/ERK, and MAPK/JNK pathways, etc.300,301 Activation of these molecular signaling cascades promotes the initiation of a series of cellular biological behaviors, such as LEC proliferation and migration and vessel sprouting (Fig. 13). VEGFA has been identified as the angiogenic factor acting via VEGFR1 and VEGFR2. Some recent work revealed that VEGFA promotes LEC proliferation and migration and lympangiogenesis.302–305 On one hand, VEGFA could function on VEGFR1/2 expressed by LECs and promote lymphanigongenesis.304,305 On the other hand, VEGFA could indirectly induce lymphangiogenesis via recruitment of VEGFR1+ bone marrow-derived macrophages which in turn release both hemangiogenic and lymphangiogenic growth factors.302,303Fig. 13 Lymphangiogenesis-mediating proteins ligands and their receptors. Schematic diagram showing the main promoters of lymphangiogenesis with soluble ligands or interacting proteins present outside the cell and the transmembrane receptors expressed by lymphatic endothelial cells (LECs) at 7the cell surface. VEGFC vascular endothelial growth factor C, VEGFD vascular endothelial growth factor D, VEGFR3 vascular endothelial growth factor receptors 3, ANG angiopoietin, TIE, tunica interna endothelial cell kinase, EGF epidermal growth factor, EGFR epidermal growth factor receptor, FGF fibroblast growth factor, FGFR fibroblast growth factor receptor, HGF hepatocyte growth factor, PDGF platelet-derived growth factor, PDGFR platelet-derived growth factor receptor, IGF insulin-like growth factor, IGFR insulin-like growth factor receptor, AM adrenomedullin. Created with BioRender.com

Targeted inhibitors of VEGF signaling

Antibody drugs: Bevacizumab is a well-characterized monoclonal antibody of VEGFs and is used as an anti-angiogenic drug for various types of cancer. Moreover, some clinical trials have been carried out to evaluate its anti-lymphangiogenic effects.306 Dumond et al. reported a new VEGFC antibody named 1E9 that significantly inhibited VEGFR3 signaling activation in LECs.307 Similarly, VGX-100, another highly specific monoclonal antibody, targeted VEGFC and impaired VEGFC-VEGFR2/3 signaling activation.308 A soluble fusion protein VEGFR3-immunoglobulin that bound VEGFC and inhibited VEGFR3 signaling has also been reported, and their effects in inhibiting tumor lymphangiogenesis and metastasis were remarkable.309 To target VEGFRs, blocking VEGFR3 signaling with VEGFR3 antagonist antibodies effectively inhibited angiogenesis, lymphangiogenesis, and tumor growth in an orthotopic spontaneous breast cancer metastasis model.310

Small-molecule inhibitors: The FDA has approved several small-molecule inhibitors of VEGFRs because they significantly prolong the survival of cancer patients. For instance, pazopanib is an orally available small-molecule inhibitor of VEGFRs, including VEGFR1, VEGFR2, and VEGFR3. Pazopanib showed favorable inhibitory effects on tumor growth, lymph node metastasis, and tumor lymphangiogenesis in an orthotopic colorectal cancer model.311 Sunitinib is a small-molecule inhibitor that targets VEGFRs, PDGFRs, and c-Kit.312 Sunitinib treatment markedly reduced pathological corneal lymphangiogenesis and angiogenesis.313 However, Dufies et al. reported that sunitinib treatment also induced lymphangiogenesis in the renal cell carcinoma context by activating VEGFC transcription and stabilizing VEGFC mRNA.314

Other inhibitors: Previous studies revealed that inhibition of VEGFC with specific siRNAs reduced the lymphangiogenesis in a murine mammary tumor model.315,316 Additionally, treatment with VEGFC siRNA effectively reduced lymphangiogenesis and significantly increased the survival rate of tumor-bearing mice. Fucoxanthin, a multifunctional natural non-pro-vitamin A carotenoid, has been shown to decrease tumor-associated lymphangiogenesis, indicating a potential anti-lymphangiogenic agent for use in cancer therapy.317 Shikonin, another natural compound isolated from the traditional Chinese medicinal herb Lithospermum erythrorhizon, inhibited lymphangiogenesis in a dose- and time-dependent manner.318 Curcumin, a natural dietary compound derived from turmeric, also inhibited lymphangiogenesis in vitro and in vivo by inhibiting the expression of VEGF receptors (Table 4).319Table 4 Inhibitors of lymphangiogenesis and applications

Inhibitor name	Target of action	Application	
Antibody drugs	
Bevacizumab	VEGF	Inhibition of Corneal inflammatory lymphangiogenesis Inhibition of melanoma-associated lymphangiogenesis	
1E9	VEGFC	Inhibition of lymphangiogenesis in clear cell renal cell carcinoma	
VGX-100	VEGFC	Suppression of lymphangiogenesis in corneal graft rejection response Inhibition of lymphangiogenesis in colorectal cancer	
Single-chain fragment of VEGFC antibody	VEGFC	Blockage the lymphangiogenic activity of VEGFC	
VEGFR3-immunoglobulin	VEGFC	Suppression of lung cancer-associated lymphangiogenesis	
VEGFR3 antagonist antibody	VEGFR3	Suppression of lung cancer-associated lymphangiogenesis	
MEDI3617	ANG2	Reduction of lung cancer-associated lymphangiogenesis	
AZD5180	ANG2	Inhibition of lymphangiogenesis in infection-mediated inflammation	
18E5	ANG2	Suppression of lymphangiogenesis in corneal graft rejection response	
Small molecular inhibitors	
Pazopanib	VEGFR1, VEGFR2, VEGFR3	Inhibition of lymphangiogenesis in colorectal cancer	
Sunitinib	VEGFR1, VEGFR2, VEGFR3, PDGFRs, c-Kit	Suppression of pathologic corneal lymphangiogenesis, Suppression of cancer-associated lymphangiogenesis	
Synthesized preclinical candidate agents	
VEGFC siRNA	VEGFC	Suppression of lymphangiogenesis	
ANG2 siRNA	ANG2	Suppression of pathologic corneal lymphangiogenesis	
Inhibitors naturally existed in the host	
WNT1	VEGFC	Inhibition of melanoma-associated lymphangiogenesis	
TSP-1	VEGFC	Suppression of corneal lymphangiogenesis Inhibition of lymphangiogenesis in mouse atherosclerotic aortic tissue	
Semaphorins	Plexins and NRPs	Suppression of corneal lymphangiogenesis Suppression of HNSCC-associated lymphangiogenesis	
IFN-γ		Promotion of LEC apoptosis	
Other inhibitors	
Rapamycin	mTOR	Inhibition of cancer-associated lymphangiogenesis Suppression of lymphangiogenesis in corneal graft rejection response	
Celecoxib	COX2	Suppression of lymphangiogenesis in breast cancer	
Aspirin	COXs	Suppression of lymphangiogenesis in lung cancer	
Phomaketide A	VEGFR3 PKCδ, eNOS	Inhibition of cancer-associated lymphangiogenesis	
Fucoxanthin	-	Suppression of lymphangiogenesis in breast cancer	
Shikonin	NF-κB	Inhibition of lymphangiogenesis in an in vitro model	
Curcumin	VEGFR3	Suppression of cancer-associated lymphangiogenesis	
VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor, ANG angiopoietin, PDGFR platelet-derived growth factor receptor, NRP neuropilin, mTOR mammalian target of rapamycin, COX cyclooxygenase, PKC δ protein kinase C δ, eNOS endothelial nitric oxide synthase

ANG

Agonistic effects of ANG

ANG and its receptors were first found to be important modulators in blood vessel growth, maturation, and stability. The two ANG receptors, called TIE1 and TIE2, were also reported to be expressed in LECs. After interaction with TIE on LECs, ANG induced the formation of TIE receptor complexes and then mediated cell behavior via activation of the PI3K/AKT pathway. AKT subsequently phosphorylated FOXO1, causing its nuclear exclusion and reducing the expression of FOXO1 downstream genes.320 Some findings revealed that ANG1 promoted lymphangiogenesis dependent on VEGFR3, indicating a difference in effects between ANG proteins.321 Interestingly, a recent study revealed that VEGFC induced ANG2 secretion from LECs and then stabilized VEGFR3 expression via the activation of ANG2/TIE/PI3K signaling, revealing cross-talk between the VEGFC and ANG2 signaling pathways.322 Additionally, ANG2 also functioned independent of its binding to TIE receptors. In this scenario, ANG2 bound β1 integrin and activated Src and FAK, leading to RhoA activation. The activation of RhoA led to the phosphorylation of the downstream effectors ROCK and formins, thereby regulating lymphangiogenesis.323

Targeted inhibitors of ANG signaling

Antibody drugs: Considering the effects of ANG2 on angiogenesis and lymphangiogenesis, several neutralizing antibodies for this signaling pathway have been designed and synthesized. These antibodies include trebananib, CVX-060, AMG 780, MEDI3617, Nesvacumab, Aflibercept, CVX-241, AZD5180, and 18E5. Among these neutralizing antibodies, MEDI3617, AZD5180, and 18E5 have been reported to show significant inhibitory effects on lymphangiogenesis.324,325

Small-molecule inhibitors: Regorafenib is a novel oral multikinase inhibitor that can inhibit various kinases, including VEGFRs, TIE, PDGFRs, c-Kit, BRAF, etc.326 In orthotopic colon tumor models, regorafenib treatment significantly decreased the density of lymphatic vessels in tumors.327

Other inhibitors: A previous study showed that siRNA-mediated ANG2 knockdown markedly inhibited corneal lymphangiogenesis.76 Recently, some multifunctional siRNA nanocapsules have been developed to deliver siRNA for targeting ANG in glioblastoma,328,329 which may provide a new direction for delivering siRNA for the treatment of abnormal lymphangiogenesis (Table 4).

Epidermal growth factor (EGF)

Agonistic effects of EGF

EGF belongs to a group of growth factors that specifically bind EGFR and activate EGFR signaling,330 which has been reported to participate in regulating skin lymphangiogenesis. EGF notably facilitated pathological lymphangiogenesis in melanoma, thus supporting the lymph node metastasis of melanoma.331 In summary, the effects of EGF on lymphangiogenesis have been relatively less studied than the effects of other factors and remain to be further investigated in the future.

Targeted inhibitors of EGF signaling

Antibody drugs: Some preclinical evidence has shown that monoclonal antibodies targeting EGF signaling could attenuate angiogenesis during cancer progression.332,333 However, evidence showing the inhibitory role of these monoclonal antibodies on lymphangiogenesis is lacking and further exploration is needed.

Small-molecule inhibitors: Afatinib, erlotinib, gefitinib, lapatinib, and vandetanib are representative small-molecule inhibitors of EGFR that prevent signal transduction after ligand-receptor binding and EGFR dimer formation. Among these drugs, lapatinib has been reported to attenuate tumor lymphangiogenesis and angiogenesis (Table 4).334

FGF2

FGF2 has been reported to exert a profound effect on lymphangiogenesis. In the mouse cornea, FGF2 promoted lymphangiogenesis in a dose-dependent manner and enhanced the secretion of VEGFC from vascular endothelial and perivascular cells to facilitate lymphangiogenesis.335 Additionally, FGF2 functions by binding the cell membrane LYVE1 with high affinity, which subsequently induces lymphangiogenesis.336

Hepatocyte growth factor (HGF)

HGF is a heparin-binding glycoprotein that was first shown to mediate liver regeneration. HGF functions by interacting with HGFR (also known as c-Met) to regulate lymphangiogenesis. Supplementation of HGF into the LEC culture medium promoted lymphangiogenesis, while inhibition of HGFR with an antagonist reduced the lymphangiogenesis.337

PDGF

PDGFs are secreted dimeric glycoprotein ligands with biological activities mediated by three forms of tyrosine kinase receptors encoded by two gene products, PDGFR-α and PDGFR-β.338,339 PDGF-BB functions as a lymphangiogenic factor and directly binds PDGFR-β expressed on LECs to induce lymph vessel growth.340

The insulin growth factor (IGF)

IGF signaling pathway is composed mainly of IGFs (IGF1 and IGF2), IGFRs (IGFR1, and IGFR2), and IGF-binding proteins (IGFBPs).341,342 IGFs bind IGFRs to initiate their effects, while IGFBPs interact with IGFs to modulate IGF stability and activity. IGFRs are expressed by LECs in both humans and mice. In vivo, administration of IGFs stimulated lymph vessel network expansion, while in vitro treatment with IGFs increased the lymphangiogenesis via activation of downstream ERK and PI3K/AKT signaling.343 In the future, the development of IGFs, IGFRs or IGFBPs antagonists may be an important approach for treating abnormal lymphangiogenesis.

WNT

Among the WNT family members, WNT5A and WNT5B have been reported to exert a positive effect on lymphangiogenesis.344,345 WNT5A regulates dermal lymphangiogenesis mainly through the noncanonical β-catenin-independent signaling pathway.346 Cancer cell-derived WNT5B modulated lymphangiogenesis and lymphatic permeability through the activation of both canonical and noncanonical WNT signaling pathways.344

EphrinB2

EphrinB2, a transmembrane ligand of the Eph receptor EphB4, controls cell migration and cytoskeletal organization in many different cell types and tissues.347,348 Evidence has shown that EphrinB2 and EphB4 are simultaneously expressed by endothelial cells and promote sprouting behavior to induce angiogenesis and lymphangiogenesis.349,350 Mechanistically, the binding of EphrinB2 to EphB4 promoted the activation of the small GTPases Rac1, AKT, and ERK and promoted VEGFC/VEGFR3 downstream signaling. In capillary lymphatic vessels of adult mouse corneas, the EphrinB2/EphB4 axis functioned in the formation and maintenance of funnel-shaped valves, indicating that this axis might be an ideal target for regulating corneal lymphangiogenesis.351

Adrenomedullin

Adrenomedullin, a well-known vasodilator, is also an important regulator of lymphangiogenesis. Adrenomedullin functions by binding its specific receptor, CALCRL. Ablation of Adrenomedullin/CALCRL signaling impedes the activation of ERK signaling, leading to the formation of abnormal jugular lymphatic vessels.63 Blockade of Adrenomedullin/CALCRL signaling after normal lymphatic vessel formation resulted in impaired permeability and function in intestinal, corneal, and dermal lymphatic vessels.352 In several types of cancers, Adrenomedullin significantly increased tumor-associated lymphangiogenesis.353,354

Bioactive lipids

Bioactive lipids are important regulators in the body; they include 1) arachidonic acid (AA) and its metabolites, such as prostaglandins (PGs), thromboxane (TXA), and leukotrienes (LTs); 2) S1P, a metabolic product of sphingolipids; and 3) lysophosphatidic acid (LPA). These bioactive lipids have been shown to regulate lymphangiogenesis under certain pathological conditions. We summarize the function of these common bioactive lipids in lymphangiogenesis (Fig. 14).Fig. 14 The role of bioactive lipids and ncRNAs on lymphangiogenesis. a The bioactive lipids derived from the metabolism of arachidonic acid, Sphingosine, phosphatidic acid could regulate lymphangiogenesis through binding their specific GPCRs; b The function model of ncRNAs on lymphangiogenesis. Some ncRNAs were reported to have evident role on lyphangiogenesis, especially in tumor associated-lymphangiogenesis. These ncRNAs could be potential therapeutic targets for controlling abnormal lymphangiogenesis in cancer. GPCRs G Protein-Coupled Receptors, COX cyclooxygenase, PLA2 phospholipase A2, PS prostanoid synthases, TXA thromboxane, LOX5 5-lipoxygenase, S1P sphingosine 1-phosphate, LPA lysophosphatidic acid, ncRNAs noncoding RNAs, lncRNAs long noncoding RNAs, circRNAs circular RNAs, RBPs, RNA binding proteins. Created with BioRender.com

PGs

PGs are common metabolites of AA generate through the action of phospholipase A2, cyclooxygenases (COXs), and the respective prostanoid synthases. PGs function by binding their specific receptors, which are often transmembrane G protein-coupled receptors.355,356 In an LPS-induced model of inflammation, COX2-derived PGs enhanced lymphangiogenesis.357 Similarly, in acute colitis induced by DSS, PGE2/PGE receptor (EP) 4 signaling stimulates lymphangiogenesis to repair damaged mucosa. PGE2-EP4 activation on tumor cells and TAMs increased the amount of VEGFC and VEGFD secreted from these cells and then stimulated LEC lymphangiogenesis.358 Tumor-derived PGE2 also directly acted on LECs to activate EP4 and VEGFR3 and ultimately induced lymphangiogenesis.359

TXA2

TXA2 is an unstable metabolite of AA produced by the reciprocal action of COX and TX synthase.360,361 TXA2 plays a regulatory role by binding thromboxane prostanoid (TP), a transmembrane G protein-coupled receptor. TXA2-TP signaling facilitates lymphangiogenesis by acting on macrophages and T cells during inflammation. TP-positive macrophages and T cells infiltrate inflamed tissue and produce VEGFC and VEGFD after stimulation with TXA2. These macrophage- and T-cell-derived VEGFC/D promoted lymphangiogenesis and drainage function in mice with inflammatory stress.362

LTs

LTs constitute a class of bioactive lipids derived from AA by 5-lipoxygenase (LOX5) and LOX5-activating protein.363,364 LTs also function by binding G protein-coupled receptors. Two G protein-coupled receptors, BLT1 and BLT2, are receptors for LTB4 and are expressed in macrophages, leukocytes, epidermal keratinocytes, and epithelial cells. Evidence from a lymphedema model showed that macrophages are important sources of LTB4 and that inhibition of LTB4 signaling effectively prevents edema.365,366

S1P

S1P is the phosphorylated form of sphingosine that is formed through the action of sphingosine kinase 1 (SphK1) and SphK2. S1P not only functions intracellularly as a second messenger, but also can be exported extracellularly to serve as a ligand for a family of S1P receptors.367 S1P promotes lymphangiogenesis both in vitro and in vivo through the S1P/Gi/phospholipase C/Ca2+ signaling pathways.368 In breast cancer, SphK1-mediated S1P production induced lymphangiogenesis, indicating that SphK1-S1P signaling may be a potential therapeutic target for controlling lymphangiogenesis.369

LPA

LPA is a low-molecular-weight lipid growth factor that functions by binding to Edg family members.370 LPA is generated through enzymatic cleavage of membrane phosphatidic acid. A series of studies have revealed that LPA promoted lymphangiogenesis by increasing the expression of the important prolymphangiogenic factor VEGFC in targeted cells such as tumor cells and endothelial cells.371,372

NcRNA

NcRNA transcripts constitute a recently described type of RNA that has been extensively explored in recent decades. Some ncRNAs have been reported to play a clear role in lymphangiogenesis, especially in tumor-associated lymphangiogenesis (Fig. 14).

LncRNAs

LncRNAs are RNA transcripts longer than 200 bases with low protein-coding potential.373 Some lncRNAs play a prolymphangiogenic role intracellularly to enhance the expression of VEGFC, thereby promoting lymphangiogenesis.374,375 Cancer cells also deliver lncRNA-containing exosomes to LECs. The lncRNA cargo internalized by LECs induced lymphangiogenesis both in vitro and in vivo.376 These pieces of evidence implicate lncRNAs as important therapeutic targets for controlling abnormal lymphangiogenesis in patients with cancer (Fig. 14).

CircRNAs

CircRNAs represent a type of novel ncRNA with a covalently circular structure generated from the splicing of pre-mRNAs and interlacing of the 5′ caps and 3′ poly-A tails and are specific messenger RNAs.377,378 The role of circRNAs in lymphangiogenesis was investigated recently. For instance, circEHBP1 served as a miRNA sponge for miR-130a-3p to regulate the TGFβR1/VEGFD axis, leading to increased levels of VEGFD and lymph vessel density in the context of bladder cancer.203 Additionally, some circRNAs are transported from cancer cells to LECs via exosomes. In this manner, cancer cell-derived circRNAs can directly function as intra-LECs to contribute to lymphangiogenesis.379

Clinical trials of treatments for lymphangiogenesis-related diseases

We conducted an electronic search for relevant clinical trials of lymphangiogenesis-related diseases in PubMed. Additionally, relevant clinical trial registration sites, such as ClinicalTrials.gov and Netherlands Trial Registry, were comprehensively examined. Literature retrieval was performed in duplicate by two independent reviewers. A total of ten published clinical trials were included in the analysis, and among these, seven studies mainly examined the effects of different interventions on lymphangiogenesis-related diseases in human samples, one study focused on evaluating stem cell therapy in lymphedema,380 one study focused on circulating angiogenic factors in pulmonary tuberculosis in which angiogenesis and lymphangiogenesis were classical features,381 and one study mainly examined whether PDPN expression correlated with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx.382 The characteristics of these studies are listed in Supplementary Table 1.

The ten selected clinical trials had enrolled participants with eight different diseases and conditions. More than three studies enrolled participants with breast cancer, including HER2-negative breast cancer and lymph node-positive breast cancer.383–385 A few studies recruited participants with other diseases, including lung adenocarcinoma,386 early squamous cell carcinomas of the oral cavity and oropharynx, Type 1 diabetes,252 tongue cancer,387 lower limb lymphedema, lymphangioleiomyomatosis (LAM)388 and pulmonary tuberculosis. The study with the largest number of participants enrolled patients with centrally located squamous cell carcinoma with cavitary features, and those with brain metastases that were uncontrolled or controlled for less than 2 months were excluded (n = 440). The patients were randomly assigned in a 2-to-1 ratio to receive either 12 mg/day of anlotinib (n = 294) or a matched placebo (n = 146).

With regard to the intervention/comparison in the studies, over half of the studies (n = 5) focused on drug (anlotinib treatment for lung adenocarcinoma) and stem cell therapy (using bone marrow-derived mononuclear cells in the treatment of lower limb lymphedema), and 1 study focused on dietary interventions such as salt intake. Salt-sensitive blood pressure increases in Type 1 diabetes patients is accompanied by disturbed skin macrophage influx and lymphatic dilation. In an evaluation of the medical treatment of patients with breast cancer, two clinical trials demonstrated that treatment with sunitinib showed favorable effects on tumor vessel modulation and lymphangiogenesis and significantly decreased lymphatic vessel density, as assessed via immunohistochemistry. To assess a lung adenocarcinoma medical treatment, one clinical trial demonstrated that anlotinib suppressed lymphangiogenesis and lymphatic metastasis through a process potentially involving VEGFR3 signaling. Another clinical trial showed that in patients with lymphangioleiomyomatosis, sirolimus stabilized lung function and reduced the level of serum VEGFD, which is a lymphangiogenic growth factor implicated in the pathophysiology of LAM and was associated with a reduction in symptoms and improvement in quality of life. A study of patients with chronic lymphedema showed that cell therapy led to reduced limb circumference and increased pain relief and improved walking ability compared with the results in the control group.

Approximately 40.0% (n = 4) of published clinical trials explored the effects of lymphangiogenesis activators under pathological conditions. One study showed that HER2/neu expression correlated with VEGFC and lymphangiogenesis in lymph node-positive breast cancer patients. Another study demonstrated that pulmonary tuberculosis was associated with elevated circulating levels of VEGFA, VEGFC, and VEGFR2, and angiogenesis and lymphangiogenesis were shown to be classical features of granuloma formation. Recently, the expression of PDPN in cancer cells was demonstrated to promote tumor cell motility and tumor lymphangiogenesis in vitro, and one supplementary clinical trial showed that PDPN expression correlated with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx. NRP2 plays an important role in regulating lymphangiogenesis, and findings from a clinical trial for patients with early-stage tongue cancer showed that cytoplasmic NRP2 was associated with metastasis and a poor prognosis.

Although several published clinical trials showed consistent findings and most studies suggested that drug interventions targeting activators or inhibitors suppressed lymphangiogenesis-related signaling, lymphangiogenesis activators played an important role in attenuating the pathological state. Given the substantial impact of lymphangiogenesis progression on health and disease, a larger sample, longer intervention period, and multicenter clinical trials are needed to examine the safety and efficacy of targeted interventions.

Conclusion

Since the discovery of lymphatic vessels exists in organisms, an increasing number of studies have revealed the mapping of lymphatic vessel anatomy and development. In this review, we described the general lymphatic vessel development and regulatory signaling pathways. Meanwhile, organ-specific lymphatic vessel development has also shown heterogeneous processes and signaling regulation catering to tissue development and physiological functions. However, the lymphangiogenic regulatory landscape remains a puzzle. Therefore, further mechanism studies are required to determine the phenotypic differences of lymphatic vessels in diverse developmental stages and tissues, including the key transcriptome and epigenome function. The robust lymph absorption and transport capacity of lymphatic vessels contribute to fluid homeostasis. In addition, lymphatic vessels directly or indirectly participate in immunosurveillance and immune response within diverse tissues and organs.

Lymphatic vessels are actively involved in multiple diseases in humans and alleviate or exacerbate local pathological progression through lymphangiogenesis. Notably, many studies have great interest in exploring lymphangiogenesis in tumors, which actively participates in the process of lymph node metastasis and affects the tumor prognosis and treatment. Moreover, LECs are involve in the regulation of tumor-specific immune response by affecting migration, function, and survival of immune cells. Exploration of crosstalk between LECs and immune cells may be a powerful target to enhance immunosurveillance for tumors in humans. In the future, exploration of the specific markers for tumor-associated lymphangiogenesis assists clinical tracing of metastatic lymph nodes, which may provide the specification for accurate lymph node resection. Targeting lymphangiogenesis is a potential and powerful intervention for restoring lymphatic vessel function and improving disease treatment. Based on these, we systematically review the lymphangiogenic signaling pathways, with specific inhibitors known till now. Moreover, multi-center clinical trials are being carried out to further demonstrate the feasibility and broad prospects of targeting abnormal lymphangiogenesis in a variety of diseases.

In conclusion, we have summarized the heterogeneous characteristics and functions of lymphatic vessels in health and disease conditions and expect to provide comprehensive knowledge for future research to realize translational therapy.

Supplementary information

Supplemental Table 1

Supplementary information

The online version contains supplementary material available at 10.1038/s41392-023-01723-x.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (U22A20324,82202927) and Excellent Youth Foundation of Liaoning Province (2022-YQ-15). We acknowledge the use of Adobe Illustrator for creating Figs. 1–10 and BioRender.com for creating Figs. 11–14.

Author contributions

Z.N.W., Y.X.S. and Y.N.X. supervised this work. Z.L.H. and X.S.Z. wrote/revised the manuscript and designed the figures and tables. Z.H.W. checked and polished the manuscript. B.C.Q. and M.X.Y. helped search and summarize the relative literature. All authors have read and approved the article.

Competing interests

The authors declare no competing interests.

These authors contributed equally: Zhaoliang Hu, Xushi Zhao, Zhonghua Wu
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References

1. Breslin JW Lymphatic vessel network structure and physiology Compr. Physiol. 2018 9 207 299 30549020
Breslin, J. W. et al. Lymphatic vessel network structure and physiology. Compr. Physiol. 9, 207–299 (2018).30549020
2. Oliver G Kipnis J Randolph GJ Harvey NL The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease Cell 2020 182 270 296 32707093
Oliver, G., Kipnis, J., Randolph, G. J. & Harvey, N. L. The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease. Cell 182, 270–296 (2020).32707093
3. Natale G Bocci G Ribatti D Scholars and scientists in the history of the lymphatic system J. Anat. 2017 231 417 429 28614587
Natale, G., Bocci, G. & Ribatti, D. Scholars and scientists in the history of the lymphatic system. J. Anat. 231, 417–429 (2017).28614587
4. Irschick R Siemon C Brenner E The history of anatomical research of lymphatics—from the ancient times to the end of the European Renaissance Ann. Anat. 2019 223 49 69 30731199
Irschick, R., Siemon, C. & Brenner, E. The history of anatomical research of lymphatics—from the ancient times to the end of the European Renaissance. Ann. Anat. 223, 49–69 (2019).30731199
5. Kanter MA The lymphatic system: an historical perspective Plast. Reconstr. Surg. 1987 79 131 139 3541012
Kanter, M. A. The lymphatic system: an historical perspective. Plast. Reconstr. Surg. 79, 131–139 (1987).3541012
6. Sheldon, J. The history of the absorbent system part the first. Containing the chylography, or description of the human lacteal vessels, with the different methods of discovering, injecting, and preparing them, and the instruments used for these purposes. (1784).
7. Chikly B Who discovered the lymphatic system Lymphology 1997 30 186 193 9476250
Chikly, B. Who discovered the lymphatic system. Lymphology 30, 186–193 (1997).9476250
8. Massa, N. Liber introductorius anatomiae siue dissectionis corporis humani. (1536).
9. Eustachius, B. Opuscula anatomica. (1564).
10. Anderson H GASPAR ASELLIUS: the discoverer of the lacteals Can. Med. Assoc. J. 1933 28 666
Anderson, H. GASPAR ASELLIUS: the discoverer of the lacteals. Can. Med. Assoc. J. 28, 666 (1933).
11. Gans H On the discovery of the lymphatic circulation Angiology 1962 13 530 536 13946413
Gans, H. On the discovery of the lymphatic circulation. Angiology 13, 530–536 (1962).13946413
12. Pecqueti, J. Experimenta nova anatomica, quibus incognitum hactenus chyli receptaculum, & ab eo per thoracem in ramos usque subclavios vasa lactea deteguntur. (1700).
13. Eriksson G Olaus Rudbeck as scientist and professor of medicine Sven. Med. Tidskr. 2004 8 39 44 16025602
Eriksson, G. Olaus Rudbeck as scientist and professor of medicine. Sven. Med. Tidskr. 8, 39–44 (2004).16025602
14. Fulton, J. F. The early history of the lymphatics: with particular reference to Bartholin, Rudbeck and Joyliffe. (1938).
15. Bartholin, T. Vasa lymphatica: Nuper Hafniae in Animantibus inventa, Et Hepatis exseqviae. (1653).
16. Ruysch, F. Dilucidatio valvularum in vasis lymphaticis, et lacteis. Apud Janssonio-Waesbergios (1720).
17. Mascagni, P. Iconography and history of the lymphatic vessels of the human body. Siena, Italy: Pazzini Carli (1787).
18. Di Matteo B Art in science: Giovanni Paolo Mascagni and the art of anatomy Clin. Orthop. Rel. Res. 2015 473 783 788
Di Matteo, B. et al. Art in science: Giovanni Paolo Mascagni and the art of anatomy. Clin. Orthop. Rel. Res. 473, 783–788 (2015).
19. Sabin FR On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig Am. J. Anat. 1902 1 367 389
Sabin, F. R. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. Am. J. Anat. 1, 367–389 (1902).
20. Huntington GS McClure CFW The anatomy and development of the jugular lymph sacs in the domestic cat (Felis domestica) Am. J. Anat. 1910 10 177 312
Huntington, G. S. & McClure, C. F. W. The anatomy and development of the jugular lymph sacs in the domestic cat (Felis domestica). Am. J. Anat. 10, 177–312 (1910).
21. Ny A A genetic Xenopus laevis tadpole model to study lymphangiogenesis Nat. Med. 2005 11 998 1004 16116431
Ny, A. et al. A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nat. Med. 11, 998–1004 (2005).16116431
22. Schneider M Othman-Hassan K Christ B Wilting J Lymphangioblasts in the avian wing bud Dev. Dyn. 1999 216 311 319 10633852
Schneider, M., Othman-Hassan, K., Christ, B. & Wilting, J. Lymphangioblasts in the avian wing bud. Dev. Dyn. 216, 311–319 (1999).10633852
23. Küchler AM Development of the zebrafish lymphatic system requires VEGFC signaling Curr. Biol. 2006 16 1244 1248 16782017
Küchler, A. M. et al. Development of the zebrafish lymphatic system requires VEGFC signaling. Curr. Biol. 16, 1244–1248 (2006).16782017
24. Yaniv K Live imaging of lymphatic development in the zebrafish Nat. Med. 2006 12 711 716 16732279
Yaniv, K. et al. Live imaging of lymphatic development in the zebrafish. Nat. Med. 12, 711–716 (2006).16732279
25. Ducoli L Detmar M Beyond PROX1: transcriptional, epigenetic, and noncoding RNA regulation of lymphatic identity and function Dev. Cell 2021 56 406 426 33621491
Ducoli, L. & Detmar, M. Beyond PROX1: transcriptional, epigenetic, and noncoding RNA regulation of lymphatic identity and function. Dev. Cell 56, 406–426 (2021).33621491
26. Srinivasan RS Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature Genes Dev. 2007 21 2422 2432 17908929
Srinivasan, R. S. et al. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 21, 2422–2432 (2007).17908929
27. Hägerling R A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy EMBO J. 2013 32 629 644 23299940
Hägerling, R. et al. A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J. 32, 629–644 (2013).23299940
28. Stone OA Stainier DYR Paraxial mesoderm is the major source of lymphatic endothelium Dev. Cell 2019 50 247 255.e3 31130354
Stone, O. A. & Stainier, D. Y. R. Paraxial mesoderm is the major source of lymphatic endothelium. Dev. Cell 50, 247–255.e3 (2019).31130354
29. Martinez-Corral I Nonvenous origin of dermal lymphatic vasculature Circ. Res. 2015 116 1649 1654 25737499
Martinez-Corral, I. et al. Nonvenous origin of dermal lymphatic vasculature. Circ. Res. 116, 1649–1654 (2015).25737499
30. Pichol-Thievend C A blood capillary plexus-derived population of progenitor cells contributes to genesis of the dermal lymphatic vasculature during embryonic development Development 2018 145 dev160184 29773646
Pichol-Thievend, C. et al. A blood capillary plexus-derived population of progenitor cells contributes to genesis of the dermal lymphatic vasculature during embryonic development. Development 145, dev160184 (2018).29773646
31. Stanczuk L cKit lineage hemogenic endothelium-derived cells contribute to mesenteric lymphatic vessels Cell Rep. 2015 10 1708 1721 25772358
Stanczuk, L. et al. cKit lineage hemogenic endothelium-derived cells contribute to mesenteric lymphatic vessels. Cell Rep. 10, 1708–1721 (2015).25772358
32. Klotz L Cardiac lymphatics are heterogeneous in origin and respond to injury Nature 2015 522 62 67 25992544
Klotz, L. et al. Cardiac lymphatics are heterogeneous in origin and respond to injury. Nature 522, 62–67 (2015).25992544
33. Maruyama K Isl1-expressing non-venous cell lineage contributes to cardiac lymphatic vessel development Dev. Biol. 2019 452 134 143 31112709
Maruyama, K. et al. Isl1-expressing non-venous cell lineage contributes to cardiac lymphatic vessel development. Dev. Biol. 452, 134–143 (2019).31112709
34. Lioux G A second heart field-derived vasculogenic niche contributes to cardiac lymphatics Dev. Cell 2020 52 350 363.e6 31928974
Lioux, G. et al. A second heart field-derived vasculogenic niche contributes to cardiac lymphatics. Dev. Cell 52, 350–363.e6 (2020).31928974
35. Maruyama K The cardiopharyngeal mesoderm contributes to lymphatic vessel development in mouse Elife 2022 11 e81515 36196867
Maruyama, K. et al. The cardiopharyngeal mesoderm contributes to lymphatic vessel development in mouse. Elife 11, e81515 (2022).36196867
36. Kaipainen A Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development Proc. Natl Acad. Sci. USA 1995 92 3566 3570 7724599
Kaipainen, A. et al. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc. Natl Acad. Sci. USA 92, 3566–3570 (1995).7724599
37. Joukov V A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases EMBO J. 1996 15 1751 8612600
Joukov, V. et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 15, 1751 (1996).8612600
38. Karkkainen MJ Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins Nat. Immunol. 2004 5 74 80 14634646
Karkkainen, M. J. et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat. Immunol. 5, 74–80 (2004).14634646
39. Wigle JT Oliver G Prox1 function is required for the development of the murine lymphatic system Cell 1999 98 769 778 10499794
Wigle, J. T. & Oliver, G. Prox1 function is required for the development of the murine lymphatic system. Cell 98, 769–778 (1999).10499794
40. Breiteneder-Geleff S Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium Am. J. Pathol. 1999 154 385 394 10027397
Breiteneder-Geleff, S. et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am. J. Pathol. 154, 385–394 (1999).10027397
41. Banerji S LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan J. Cell Biol. 1999 144 789 801 10037799
Banerji, S. et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J. Cell Biol. 144, 789–801 (1999).10037799
42. Yang Y Oliver G Development of the mammalian lymphatic vasculature J. Clin. Investig. 2014 124 888 897 24590273
Yang, Y. & Oliver, G. Development of the mammalian lymphatic vasculature. J. Clin. Investig. 124, 888–897 (2014).24590273
43. Jafree DJ Long DA Scambler PJ Ruhrberg C Mechanisms and cell lineages in lymphatic vascular development Angiogenesis 2021 24 271 288 33825109
Jafree, D. J., Long, D. A., Scambler, P. J. & Ruhrberg, C. Mechanisms and cell lineages in lymphatic vascular development. Angiogenesis 24, 271–288 (2021).33825109
44. Escobedo N Oliver G Lymphangiogenesis: origin, specification, and cell fate determination Annu. Rev. Cell Dev. Biol. 2016 32 677 691 27298093
Escobedo, N. & Oliver, G. Lymphangiogenesis: origin, specification, and cell fate determination. Annu. Rev. Cell Dev. Biol. 32, 677–691 (2016).27298093
45. Ulvmar MH Mäkinen T Heterogeneity in the lymphatic vascular system and its origin Cardiovasc. Res. 2016 111 310 321 27357637
Ulvmar, M. H. & Mäkinen, T. Heterogeneity in the lymphatic vascular system and its origin. Cardiovasc. Res. 111, 310–321 (2016).27357637
46. González-Loyola A Petrova TV Development and aging of the lymphatic vascular system Adv. Drug Deliv. Rev. 2021 169 63 78 33316347
González-Loyola, A. & Petrova, T. V. Development and aging of the lymphatic vascular system. Adv. Drug Deliv. Rev. 169, 63–78 (2021).33316347
47. Belle M Tridimensional visualization and analysis of early human development Cell 2017 169 161 173.e12 28340341
Belle, M. et al. Tridimensional visualization and analysis of early human development. Cell 169, 161–173.e12 (2017).28340341
48. van den Bosch QCC van Beek JGM Kiliç E Verdijk RM Transient expression of lymphatic markers in retrobulbar intraconal orbital vasculature during fetal development Invest. Ophthalmol. Vis. Sci. 2020 61 22 32516408
van den Bosch, Q. C. C., van Beek, J. G. M., Kiliç, E. & Verdijk, R. M. Transient expression of lymphatic markers in retrobulbar intraconal orbital vasculature during fetal development. Invest. Ophthalmol. Vis. Sci. 61, 22 (2020).32516408
49. Schlereth SL Absence of lymphatic vessels in the developing human sclera Exp. Eye Res. 2014 125 203 209 24975208
Schlereth, S. L. et al. Absence of lymphatic vessels in the developing human sclera. Exp. Eye Res. 125, 203–209 (2014).24975208
50. Geng X Ho Y-C Srinivasan RS Biochemical and mechanical signals in the lymphatic vasculature Cell. Mol. Life Sci. 2021 78 5903 5923 34240226
Geng, X., Ho, Y.-C. & Srinivasan, R. S. Biochemical and mechanical signals in the lymphatic vasculature. Cell. Mol. Life Sci. 78, 5903–5923 (2021).34240226
51. La H Role of transcriptional and epigenetic regulation in lymphatic endothelial cell development Cells 2022 11 1692 35626729
La, H. et al. Role of transcriptional and epigenetic regulation in lymphatic endothelial cell development. Cells 11, 1692 (2022).35626729
52. Yang Y Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos Blood 2012 120 2340 2348 22859612
Yang, Y. et al. Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos. Blood 120, 2340–2348 (2012).22859612
53. François M Sox18 induces development of the lymphatic vasculature in mice Nature 2008 456 643 647 18931657
François, M. et al. Sox18 induces development of the lymphatic vasculature in mice. Nature 456, 643–647 (2008).18931657
54. Srinivasan RS The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells Genes Dev. 2010 24 696 707 20360386
Srinivasan, R. S. et al. The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes Dev. 24, 696–707 (2010).20360386
55. Lee S Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate Blood 2009 113 1856 1859 18815287
Lee, S. et al. Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate. Blood 113, 1856–1859 (2009).18815287
56. Lin F-J Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development J. Clin. Investig. 2010 120 1694 1707 20364082
Lin, F.-J. et al. Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development. J. Clin. Investig. 120, 1694–1707 (2010).20364082
57. Srinivasan RS The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors Genes Dev. 2014 28 2175 2187 25274728
Srinivasan, R. S. et al. The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors. Genes Dev. 28, 2175–2187 (2014).25274728
58. Zhang Y Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms Nat. Commun. 2018 9 1296 29615616
Zhang, Y. et al. Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms. Nat. Commun. 9, 1296 (2018).29615616
59. Jeltsch M CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation Circulation 2014 129 1962 1971 24552833
Jeltsch, M. et al. CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation 129, 1962–1971 (2014).24552833
60. Bos FL CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo Circ. Res. 2011 109 486 491 21778431
Bos, F. L. et al. CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circ. Res. 109, 486–491 (2011).21778431
61. Yu P FGF-dependent metabolic control of vascular development Nature 2017 545 224 228 28467822
Yu, P. et al. FGF-dependent metabolic control of vascular development. Nature 545, 224–228 (2017).28467822
62. Cho H YAP and TAZ negatively regulate Prox1 during developmental and pathologic lymphangiogenesis Circ. Res. 2019 124 225 242 30582452
Cho, H. et al. YAP and TAZ negatively regulate Prox1 during developmental and pathologic lymphangiogenesis. Circ. Res. 124, 225–242 (2019).30582452
63. Fritz-Six KL Dunworth WP Li M Caron KM Adrenomedullin signaling is necessary for murine lymphatic vascular development J. Clin. Investig. 2008 118 40 50 18097475
Fritz-Six, K. L., Dunworth, W. P., Li, M. & Caron, K. M. Adrenomedullin signaling is necessary for murine lymphatic vascular development. J. Clin. Investig. 118, 40–50 (2008).18097475
64. Frye M Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program Nat. Commun. 2018 9 1511 29666442
Frye, M. et al. Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. Nat. Commun. 9, 1511 (2018).29666442
65. Planas-Paz L Mechanoinduction of lymph vessel expansion EMBO J. 2012 31 788 804 22157817
Planas-Paz, L. et al. Mechanoinduction of lymph vessel expansion. EMBO J. 31, 788–804 (2012).22157817
66. Pollitt AY Syk and Src family kinases regulate C-type lectin receptor 2 (CLEC-2)-mediated clustering of podoplanin and platelet adhesion to lymphatic endothelial cells J. Biol. Chem. 2014 289 35695 35710 25368330
Pollitt, A. Y. et al. Syk and Src family kinases regulate C-type lectin receptor 2 (CLEC-2)-mediated clustering of podoplanin and platelet adhesion to lymphatic endothelial cells. J. Biol. Chem. 289, 35695–35710 (2014).25368330
67. Hess PR Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life J. Clin. Investig. 2014 124 273 284 24292710
Hess, P. R. et al. Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life. J. Clin. Investig. 124, 273–284 (2014).24292710
68. Cha B YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling Development 2020 147 dev195453 33060128
Cha, B. et al. YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling. Development 147, dev195453 (2020).33060128
69. Vittet D Lymphatic collecting vessel maturation and valve morphogenesis Microvasc. Res. 2014 96 31 37 25020266
Vittet, D. Lymphatic collecting vessel maturation and valve morphogenesis. Microvasc. Res. 96, 31–37 (2014).25020266
70. Angeli V Lim HY Biomechanical control of lymphatic vessel physiology and functions Cell Mol. Immunol. 2023 20 1051 1062 37264249
Angeli, V. & Lim, H. Y. Biomechanical control of lymphatic vessel physiology and functions. Cell Mol. Immunol. 20, 1051–1062 (2023).37264249
71. Norden PR Shear stimulation of FOXC1 and FOXC2 differentially regulates cytoskeletal activity during lymphatic valve maturation Elife 2020 9 e53814 32510325
Norden, P. R. et al. Shear stimulation of FOXC1 and FOXC2 differentially regulates cytoskeletal activity during lymphatic valve maturation. Elife 9, e53814 (2020).32510325
72. Hernández Vásquez MN Transcription factor FOXP2 is a flow-induced regulator of collecting lymphatic vessels EMBO J. 2021 40 e107192 33934370
Hernández Vásquez, M. N. et al. Transcription factor FOXP2 is a flow-induced regulator of collecting lymphatic vessels. EMBO J. 40, e107192 (2021).33934370
73. Sabine A Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation Dev. Cell 2012 22 430 445 22306086
Sabine, A. et al. Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation. Dev. Cell 22, 430–445 (2012).22306086
74. Wang Y Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity Development 2017 144 3590 3601 28851707
Wang, Y. et al. Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity. Development 144, 3590–3601 (2017).28851707
75. Lutter S Xie S Tatin F Makinen T Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation J. Cell Biol. 2012 197 837 849 22665518
Lutter, S., Xie, S., Tatin, F. & Makinen, T. Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation. J. Cell Biol. 197, 837–849 (2012).22665518
76. Zheng W Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions Genes Dev. 2014 28 1592 1603 25030698
Zheng, W. et al. Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions. Genes Dev. 28, 1592–1603 (2014).25030698
77. Bouvrée K Semaphorin3A, Neuropilin-1, and PlexinA1 are required for lymphatic valve formation Circ. Res. 2012 111 437 445 22723296
Bouvrée, K. et al. Semaphorin3A, Neuropilin-1, and PlexinA1 are required for lymphatic valve formation. Circ. Res. 111, 437–445 (2012).22723296
78. Wong BW Zecchin A García-Caballero M Carmeliet P Emerging concepts in organ-specific lymphatic vessels and metabolic regulation of lymphatic development Dev. Cell 2018 45 289 301 29738709
Wong, B. W., Zecchin, A., García-Caballero, M. & Carmeliet, P. Emerging concepts in organ-specific lymphatic vessels and metabolic regulation of lymphatic development. Dev. Cell 45, 289–301 (2018).29738709
79. Jung HM Development of the larval lymphatic system in zebrafish Development 2017 144 2070 2081 28506987
Jung, H. M. et al. Development of the larval lymphatic system in zebrafish. Development 144, 2070–2081 (2017).28506987
80. Okuda KS lyve1 expression reveals novel lymphatic vessels and new mechanisms for lymphatic vessel development in zebrafish Development 2012 139 2381 2391 22627281
Okuda, K. S. et al. lyve1 expression reveals novel lymphatic vessels and new mechanisms for lymphatic vessel development in zebrafish. Development 139, 2381–2391 (2012).22627281
81. Nicenboim J Lymphatic vessels arise from specialized angioblasts within a venous niche Nature 2015 522 56 61 25992545
Nicenboim, J. et al. Lymphatic vessels arise from specialized angioblasts within a venous niche. Nature 522, 56–61 (2015).25992545
82. Koltowska K Vegfc regulates bipotential precursor division and prox1 expression to promote lymphatic identity in zebrafish Cell Rep. 2015 13 1828 1841 26655899
Koltowska, K. et al. Vegfc regulates bipotential precursor division and prox1 expression to promote lymphatic identity in zebrafish. Cell Rep. 13, 1828–1841 (2015).26655899
83. Hogan BM Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries Development 2009 136 4001 4009 19906867
Hogan, B. M. et al. Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries. Development 136, 4001–4009 (2009).19906867
84. Hogan BM Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting Nat. Genet. 2009 41 396 398 19287381
Hogan, B. M. et al. Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nat. Genet. 41, 396–398 (2009).19287381
85. Bussmann J Arteries provide essential guidance cues for lymphatic endothelial cells in the zebrafish trunk Development 2010 137 2653 2657 20610484
Bussmann, J. et al. Arteries provide essential guidance cues for lymphatic endothelial cells in the zebrafish trunk. Development 137, 2653–2657 (2010).20610484
86. Cha YR Chemokine signaling directs trunk lymphatic network formation along the preexisting blood vasculature Dev. Cell 2012 22 824 836 22516200
Cha, Y. R. et al. Chemokine signaling directs trunk lymphatic network formation along the preexisting blood vasculature. Dev. Cell 22, 824–836 (2012).22516200
87. Shin M Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors Development 2016 143 3785 3795 27621059
Shin, M. et al. Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors. Development 143, 3785–3795 (2016).27621059
88. Mulligan TS Weinstein BM Emerging from the PAC: studying zebrafish lymphatic development Microvasc. Res. 2014 96 23 30 24928500
Mulligan, T. S. & Weinstein, B. M. Emerging from the PAC: studying zebrafish lymphatic development. Microvasc. Res. 96, 23–30 (2014).24928500
89. Stoll SJ Bartsch S Kroll J HOXC9 regulates formation of parachordal lymphangioplasts and the thoracic duct in zebrafish via stabilin 2 PLoS One 2013 8 e58311 23484014
Stoll, S. J., Bartsch, S. & Kroll, J. HOXC9 regulates formation of parachordal lymphangioplasts and the thoracic duct in zebrafish via stabilin 2. PLoS One 8, e58311 (2013).23484014
90. Eng TC Zebrafish facial lymphatics develop through sequential addition of venous and non-venous progenitors EMBO Rep. 2019 20 e47079 30877134
Eng, T. C. et al. Zebrafish facial lymphatics develop through sequential addition of venous and non-venous progenitors. EMBO Rep. 20, e47079 (2019).30877134
91. Weigel C Bellaci J Spiegel S Sphingosine-1-phosphate and its receptors in vascular endothelial and lymphatic barrier function J. Biol. Chem. 2023 299 104775 37142226
Weigel, C., Bellaci, J. & Spiegel, S. Sphingosine-1-phosphate and its receptors in vascular endothelial and lymphatic barrier function. J. Biol. Chem. 299, 104775 (2023).37142226
92. Norden PR Kume T Molecular mechanisms controlling lymphatic endothelial junction integrity Front. Cell Dev. Biol. 2020 8 627647 33521001
Norden, P. R. & Kume, T. Molecular mechanisms controlling lymphatic endothelial junction integrity. Front. Cell Dev. Biol. 8, 627647 (2020).33521001
93. Baluk P Functionally specialized junctions between endothelial cells of lymphatic vessels J. Exp. Med. 2007 204 2349 2362 17846148
Baluk, P. et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J. Exp. Med. 204, 2349–2362 (2007).17846148
94. Hägerling R Distinct roles of VE-cadherin for development and maintenance of specific lymph vessel beds EMBO J. 2018 37 e98271 30297530
Hägerling, R. et al. Distinct roles of VE-cadherin for development and maintenance of specific lymph vessel beds. EMBO J. 37, e98271 (2018).30297530
95. Peluzzo AM Differential regulation of lymphatic junctional morphology and the potential effects on cardiovascular diseases Front. Physiol. 2023 14 1198052 37187962
Peluzzo, A. M. et al. Differential regulation of lymphatic junctional morphology and the potential effects on cardiovascular diseases. Front. Physiol. 14, 1198052 (2023).37187962
96. Stritt S Koltowska K Mäkinen T Homeostatic maintenance of the lymphatic vasculature Trends Mol. Med. 2021 27 955 970 34332911
Stritt, S., Koltowska, K. & Mäkinen, T. Homeostatic maintenance of the lymphatic vasculature. Trends Mol. Med. 27, 955–970 (2021).34332911
97. Norrmén C FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1 J. Cell Biol. 2009 185 439 457 19398761
Norrmén, C. et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J. Cell Biol. 185, 439–457 (2009).19398761
98. Johnson OW The thoracic duct: clinical importance, anatomic variation, imaging, and embolization Eur. Radiol. 2016 26 2482 2493 26628065
Johnson, O. W. et al. The thoracic duct: clinical importance, anatomic variation, imaging, and embolization. Eur. Radiol. 26, 2482–2493 (2016).26628065
99. Yao LC Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation Am. J. Pathol. 2012 180 2561 2575 22538088
Yao, L. C. et al. Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation. Am. J. Pathol. 180, 2561–2575 (2012).22538088
100. Petrova TV Koh GY Biological functions of lymphatic vessels Science 2020 369 eaax4063 32646971
Petrova, T. V. & Koh, G. Y. Biological functions of lymphatic vessels. Science 369, eaax4063 (2020).32646971
101. Oliver G Kipnis J Randolph GJ Harvey NL The lymphatic vasculature in the 21(st) century: novel functional roles in homeostasis and disease Cell 2020 182 270 296 32707093
Oliver, G., Kipnis, J., Randolph, G. J. & Harvey, N. L. The lymphatic vasculature in the 21(st) century: novel functional roles in homeostasis and disease. Cell 182, 270–296 (2020).32707093
102. Dixon JB Lymphatic lipid transport: sewer or subway? Trends Endocrinol. Met. 2010 21 480 487
Dixon, J. B. Lymphatic lipid transport: sewer or subway? Trends Endocrinol. Met. 21, 480–487 (2010).
103. Xu Y Progress on brain and ocular lymphatic system BioMed. Res. Int. 2022 2022 6413553 36425338
Xu, Y. et al. Progress on brain and ocular lymphatic system. BioMed. Res. Int. 2022, 6413553 (2022).36425338
104. Louveau A Structural and functional features of central nervous system lymphatic vessels Nature 2015 523 337 341 26030524
Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).26030524
105. Nakao S Hafezi-Moghadam A Ishibashi T Lymphatics and lymphangiogenesis in the eye J. Ophthalmol. 2012 2012 783163 22523652
Nakao, S., Hafezi-Moghadam, A. & Ishibashi, T. Lymphatics and lymphangiogenesis in the eye. J. Ophthalmol. 2012, 783163 (2012).22523652
106. Subileau M Eye lymphatic defects induced by bone morphogenetic protein 9 deficiency have no functional consequences on intraocular pressure Sci. Rep. 2020 10 16040 32994463
Subileau, M. et al. Eye lymphatic defects induced by bone morphogenetic protein 9 deficiency have no functional consequences on intraocular pressure. Sci. Rep. 10, 16040 (2020).32994463
107. Dautriche CN Tian Y Xie Y Sharfstein ST A closer look at Schlemm’s canal cell physiology: implications for biomimetics J. Funct. Biomater. 2015 6 963 985 26402712
Dautriche, C. N., Tian, Y., Xie, Y. & Sharfstein, S. T. A closer look at Schlemm’s canal cell physiology: implications for biomimetics. J. Funct. Biomater. 6, 963–985 (2015).26402712
108. Mansouri K Shaarawy T Update on Schlemm’s canal based procedures Middle East Afr. J. Ophthalmol. 2015 22 38 44 25624672
Mansouri, K. & Shaarawy, T. Update on Schlemm’s canal based procedures. Middle East Afr. J. Ophthalmol. 22, 38–44 (2015).25624672
109. Yang Y Novel discovery of a lymphatic bridge connecting Schlemm’s canal to limbal and conjunctival lymphatic pathway Ocul. Surf. 2023 29 272 278 37244593
Yang, Y. et al. Novel discovery of a lymphatic bridge connecting Schlemm’s canal to limbal and conjunctival lymphatic pathway. Ocul. Surf. 29, 272–278 (2023).37244593
110. Martin-Almedina S Mortimer PS Ostergaard P Development and physiological functions of the lymphatic system: insights from human genetic studies of primary lymphedema Physiol. Rev. 2021 101 1809 1871 33507128
Martin-Almedina, S., Mortimer, P. S. & Ostergaard, P. Development and physiological functions of the lymphatic system: insights from human genetic studies of primary lymphedema. Physiol. Rev. 101, 1809–1871 (2021).33507128
111. Bernier-Latmani J DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport J. Clin. Investig. 2015 125 4572 4586 26529256
Bernier-Latmani, J. et al. DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport. J. Clin. Investig. 125, 4572–4586 (2015).26529256
112. Zhang F Lacteal junction zippering protects against diet-induced obesity Science 2018 361 599 603 30093598
Zhang, F. et al. Lacteal junction zippering protects against diet-induced obesity. Science 361, 599–603 (2018).30093598
113. Nurmi H VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption EMBO Mol. Med. 2015 7 1418 1425 26459520
Nurmi, H. et al. VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption. EMBO Mol. Med. 7, 1418–1425 (2015).26459520
114. Kvietys PR Granger DN Role of intestinal lymphatics in interstitial volume regulation and transmucosal water transport Ann. Ny. Acad. Sci. 2010 1207 E29 E43 20961304
Kvietys, P. R. & Granger, D. N. Role of intestinal lymphatics in interstitial volume regulation and transmucosal water transport. Ann. Ny. Acad. Sci. 1207, E29–E43 (2010).20961304
115. Randolph GJ Miller NE Lymphatic transport of high-density lipoproteins and chylomicrons J. Clin. Investig. 2014 124 929 935 24590278
Randolph, G. J. & Miller, N. E. Lymphatic transport of high-density lipoproteins and chylomicrons. J. Clin. Investig. 124, 929–935 (2014).24590278
116. Lim HY Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL Cell Metab. 2013 17 671 684 23663736
Lim, H. Y. et al. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab. 17, 671–684 (2013).23663736
117. Rademakers T Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis Sci. Rep. 2017 7 45263 28349940
Rademakers, T. et al. Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis. Sci. Rep. 7, 45263 (2017).28349940
118. Ager A High endothelial venules and other blood vessels: critical regulators of lymphoid organ development and function Front. Immunol. 2017 8 45 28217126
Ager, A. High endothelial venules and other blood vessels: critical regulators of lymphoid organ development and function. Front. Immunol. 8, 45 (2017).28217126
119. Grant SM The lymph node at a glance - how spatial organization optimizes the immune response J. Cell Sci. 2020 133 jcs241828 32144196
Grant, S. M. et al. The lymph node at a glance - how spatial organization optimizes the immune response. J. Cell Sci. 133, jcs241828 (2020).32144196
120. Rouhani SJ Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction Nat. Commun. 2015 6 6771 25857745
Rouhani, S. J. et al. Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction. Nat. Commun. 6, 6771 (2015).25857745
121. Arroz-Madeira S Bekkhus T Ulvmar MH Petrova TV Lessons of vascular specialization from secondary lymphoid organ lymphatic endothelial cells Circ. Res. 2023 132 1203 1225 37104555
Arroz-Madeira, S., Bekkhus, T., Ulvmar, M. H. & Petrova, T. V. Lessons of vascular specialization from secondary lymphoid organ lymphatic endothelial cells. Circ. Res. 132, 1203–1225 (2023).37104555
122. Randolph GJ Ivanov S Zinselmeyer BH Scallan JP The lymphatic system: integral roles in immunity Annu. Rev. Immunol. 2017 35 31 52 27860528
Randolph, G. J., Ivanov, S., Zinselmeyer, B. H. & Scallan, J. P. The lymphatic system: integral roles in immunity. Annu. Rev. Immunol. 35, 31–52 (2017).27860528
123. Ulvmar MH The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes Nat. Immunol. 2014 15 623 630 24813163
Ulvmar, M. H. et al. The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes. Nat. Immunol. 15, 623–630 (2014).24813163
124. Camara A Lymph node mesenchymal and endothelial stromal cells cooperate via the RANK-RANKL cytokine axis to shape the sinusoidal macrophage niche Immunity 2019 50 1467 1481.e1466 31201093
Camara, A. et al. Lymph node mesenchymal and endothelial stromal cells cooperate via the RANK-RANKL cytokine axis to shape the sinusoidal macrophage niche. Immunity 50, 1467–1481.e1466 (2019).31201093
125. Antila S Development and plasticity of meningeal lymphatic vessels J. Exp. Med. 2017 214 3645 3667 29141865
Antila, S. et al. Development and plasticity of meningeal lymphatic vessels. J. Exp. Med. 214, 3645–3667 (2017).29141865
126. Song E Publisher Correction: VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours Nature 2021 590 E34 33500588
Song, E. et al. Publisher Correction: VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature 590, E34 (2021).33500588
127. Jacob L Anatomy and function of the vertebral column lymphatic network in mice Nat. Commun. 2019 10 4594 31597914
Jacob, L. et al. Anatomy and function of the vertebral column lymphatic network in mice. Nat. Commun. 10, 4594 (2019).31597914
128. Louveau A CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature Nat. Neurosci. 2018 21 1380 1391 30224810
Louveau, A. et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat. Neurosci. 21, 1380–1391 (2018).30224810
129. Pabst O Mowat AM Oral tolerance to food protein Mucosal Immunol. 2012 5 232 239 22318493
Pabst, O. & Mowat, A. M. Oral tolerance to food protein. Mucosal Immunol. 5, 232–239 (2012).22318493
130. Cummings RJ Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs Nature 2016 539 565 569 27828940
Cummings, R. J. et al. Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature 539, 565–569 (2016).27828940
131. Esterházy D Compartmentalized gut lymph node drainage dictates adaptive immune responses Nature 2019 569 126 130 30988509
Esterházy, D. et al. Compartmentalized gut lymph node drainage dictates adaptive immune responses. Nature 569, 126–130 (2019).30988509
132. Duhon BH Current mechanistic understandings of lymphedema and lipedema: tales of fluid, fat, and fibrosis Int. J. Mol. Sci. 2022 23 6621 35743063
Duhon, B. H. et al. Current mechanistic understandings of lymphedema and lipedema: tales of fluid, fat, and fibrosis. Int. J. Mol. Sci. 23, 6621 (2022).35743063
133. Rockson SG Cancer-associated secondary lymphoedema Nat. Rev. Dis. Prim. 2019 5 22 30923312
Rockson, S. G. et al. Cancer-associated secondary lymphoedema. Nat. Rev. Dis. Prim. 5, 22 (2019).30923312
134. Rockson SG Advances in lymphedema Circ. Res. 2021 128 2003 2016 34110905
Rockson, S. G. Advances in lymphedema. Circ. Res. 128, 2003–2016 (2021).34110905
135. Ogino R Emerging anti-inflammatory pharmacotherapy and cell-based therapy for lymphedema Int. J. Mol. Sci. 2022 23 7614 35886961
Ogino, R. et al. Emerging anti-inflammatory pharmacotherapy and cell-based therapy for lymphedema. Int. J. Mol. Sci. 23, 7614 (2022).35886961
136. Mäkinen T Boon LM Vikkula M Alitalo K Lymphatic malformations: genetics, mechanisms and therapeutic strategies Circ. Res. 2021 129 136 154 34166072
Mäkinen, T., Boon, L. M., Vikkula, M. & Alitalo, K. Lymphatic malformations: genetics, mechanisms and therapeutic strategies. Circ. Res. 129, 136–154 (2021).34166072
137. Boscolo E AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation Angiogenesis 2015 18 151 162 25424831
Boscolo, E. et al. AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation. Angiogenesis 18, 151–162 (2015).25424831
138. Ozeki M Fukao T Generalized lymphatic anomaly and Gorham-stout disease: overview and recent insights Adv. Wound Care 2019 8 230 245
Ozeki, M. & Fukao, T. Generalized lymphatic anomaly and Gorham-stout disease: overview and recent insights. Adv. Wound Care 8, 230–245 (2019).
139. Rodriguez-Laguna L Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly J. Exp. Med. 2019 216 407 418 30591517
Rodriguez-Laguna, L. et al. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. J. Exp. Med. 216, 407–418 (2019).30591517
140. Manevitz-Mendelson E Somatic NRAS mutation in patient with generalized lymphatic anomaly Angiogenesis 2018 21 287 298 29397482
Manevitz-Mendelson, E. et al. Somatic NRAS mutation in patient with generalized lymphatic anomaly. Angiogenesis 21, 287–298 (2018).29397482
141. Li D ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor Nat. Med. 2019 25 1116 1122 31263281
Li, D. et al. ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. Nat. Med. 25, 1116–1122 (2019).31263281
142. Li D Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly Hum. Mol. Genet. 2018 27 3233 3245 29905864
Li, D. et al. Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly. Hum. Mol. Genet. 27, 3233–3245 (2018).29905864
143. Dieterich LC Tacconi C Ducoli L Detmar M Lymphatic vessels in cancer Physiol. Rev. 2022 102 1837 1879 35771983
Dieterich, L. C., Tacconi, C., Ducoli, L. & Detmar, M. Lymphatic vessels in cancer. Physiol. Rev. 102, 1837–1879 (2022).35771983
144. Jiang J Immunohistochemical characterization of lymphangiogenesis-related biomarkers in primary and recurrent gliomas: a STROBE compliant article Medicines 2018 97 e12458
Jiang, J. et al. Immunohistochemical characterization of lymphangiogenesis-related biomarkers in primary and recurrent gliomas: a STROBE compliant article. Medicines 97, e12458 (2018).
145. Cohen B Transcriptional regulation of vascular endothelial growth factor C by oxidative and thermal stress is mediated by lens epithelium-derived growth factor/p75 Neoplasia 2009 11 921 933, 19724686
Cohen, B. et al. Transcriptional regulation of vascular endothelial growth factor C by oxidative and thermal stress is mediated by lens epithelium-derived growth factor/p75. Neoplasia 11, 921–933, (2009).19724686
146. Hu X Meningeal lymphatic vessels regulate brain tumor drainage and immunity Cell Res. 2020 30 229 243 32094452
Hu, X. et al. Meningeal lymphatic vessels regulate brain tumor drainage and immunity. Cell Res. 30, 229–243 (2020).32094452
147. Ramani P VEGF-C, VEGF-D and VEGFR-3 expression in peripheral neuroblastic tumours Histopathology 2012 61 1006 1016 22804730
Ramani, P. et al. VEGF-C, VEGF-D and VEGFR-3 expression in peripheral neuroblastic tumours. Histopathology 61, 1006–1016 (2012).22804730
148. Becker J Neuroblastoma progression correlates with downregulation of the lymphangiogenesis inhibitor sVEGFR-2 Clin. Cancer Res. 2010 16 1431 1441 20179233
Becker, J. et al. Neuroblastoma progression correlates with downregulation of the lymphangiogenesis inhibitor sVEGFR-2. Clin. Cancer Res. 16, 1431–1441 (2010).20179233
149. Kashima K Inhibition of lymphatic metastasis in neuroblastoma by a novel neutralizing antibody to vascular endothelial growth factor-D Cancer Sci. 2012 103 2144 2152 22937829
Kashima, K. et al. Inhibition of lymphatic metastasis in neuroblastoma by a novel neutralizing antibody to vascular endothelial growth factor-D. Cancer Sci. 103, 2144–2152 (2012).22937829
150. Sun JG Detection of lymphangiogenesis in non-small cell lung cancer and its prognostic value J. Exp. Clin. Cancer Res. 2009 28 21 19216806
Sun, J. G. et al. Detection of lymphangiogenesis in non-small cell lung cancer and its prognostic value. J. Exp. Clin. Cancer Res. 28, 21 (2009).19216806
151. Watari K Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages PLoS One 2014 9 e99568 24924428
Watari, K. et al. Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages. PLoS One 9, e99568 (2014).24924428
152. Ren S Integrin α6 overexpression promotes lymphangiogenesis and lymphatic metastasis via activating the NF-κB signaling pathway in lung adenocarcinoma Cell. Oncol. 2022 45 57 67
Ren, S. et al. Integrin α6 overexpression promotes lymphangiogenesis and lymphatic metastasis via activating the NF-κB signaling pathway in lung adenocarcinoma. Cell. Oncol. 45, 57–67 (2022).
153. Dubois C Lymph/angiogenesis contributes to sex differences in lung cancer through oestrogen receptor alpha signalling Endocr. Relat. Cancer 2019 26 201 216 30444717
Dubois, C. et al. Lymph/angiogenesis contributes to sex differences in lung cancer through oestrogen receptor alpha signalling. Endocr. Relat. Cancer 26, 201–216 (2019).30444717
154. Hu J microRNA-128 plays a critical role in human non-small cell lung cancer tumourigenesis, angiogenesis and lymphangiogenesis by directly targeting vascular endothelial growth factor-C Eur. J. Cancer 2014 50 2336 2350 25001183
Hu, J. et al. microRNA-128 plays a critical role in human non-small cell lung cancer tumourigenesis, angiogenesis and lymphangiogenesis by directly targeting vascular endothelial growth factor-C. Eur. J. Cancer 50, 2336–2350 (2014).25001183
155. Nakamura Y Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer Breast Cancer Res. Treat. 2005 91 125 132 15868440
Nakamura, Y. et al. Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer. Breast Cancer Res. Treat. 91, 125–132 (2005).15868440
156. Bieniasz-Krzywiec P Podoplanin-expressing macrophages promote lymphangiogenesis and lymphoinvasion in breast cancer Cell Metab. 2019 30 917 936.e910 31447322
Bieniasz-Krzywiec, P. et al. Podoplanin-expressing macrophages promote lymphangiogenesis and lymphoinvasion in breast cancer. Cell Metab. 30, 917–936.e910 (2019).31447322
157. Weichand B S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β J. Exp. Med. 2017 214 2695 2713 28739604
Weichand, B. et al. S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β. J. Exp. Med. 214, 2695–2713 (2017).28739604
158. Zheng S Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer J. Hematol. Oncol. 2020 13 17 32138762
Zheng, S. et al. Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer. J. Hematol. Oncol. 13, 17 (2020).32138762
159. Li J ZKSCAN5 activates VEGFC expression by recruiting SETD7 to promote the lymphangiogenesis, tumour growth, and metastasis of breast cancer Front. Oncol. 2022 12 875033 35600335
Li, J. et al. ZKSCAN5 activates VEGFC expression by recruiting SETD7 to promote the lymphangiogenesis, tumour growth, and metastasis of breast cancer. Front. Oncol. 12, 875033 (2022).35600335
160. Wang X Inhibition of NADPH oxidase 4 attenuates lymphangiogenesis and tumor metastasis in breast cancer FASEB J. 2021 35 e21531 33769605
Wang, X. et al. Inhibition of NADPH oxidase 4 attenuates lymphangiogenesis and tumor metastasis in breast cancer. FASEB J. 35, e21531 (2021).33769605
161. Sethy C Nectin-4 promotes lymphangiogenesis and lymphatic metastasis in breast cancer by regulating CXCR4-LYVE-1 axis Vasc. Pharmacol. 2021 140 106865
Sethy, C. et al. Nectin-4 promotes lymphangiogenesis and lymphatic metastasis in breast cancer by regulating CXCR4-LYVE-1 axis. Vasc. Pharmacol. 140, 106865 (2021).
162. Hou Q Extracellular Hsp90α promotes tumor lymphangiogenesis and lymph node metastasis in breast cancer Int. J. Mol. Sci. 2021 22 7747 34299365
Hou, Q. et al. Extracellular Hsp90α promotes tumor lymphangiogenesis and lymph node metastasis in breast cancer. Int. J. Mol. Sci. 22, 7747 (2021).34299365
163. Harris AR Platinum chemotherapy induces lymphangiogenesis in cancerous and healthy tissues that can be prevented with adjuvant anti-VEGFR3 therapy Front. Oncol. 2022 12 801764 35372032
Harris, A. R. et al. Platinum chemotherapy induces lymphangiogenesis in cancerous and healthy tissues that can be prevented with adjuvant anti-VEGFR3 therapy. Front. Oncol. 12, 801764 (2022).35372032
164. Sung H Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA-Cancer J. Clin. 2021 71 209 249 33538338
Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA-Cancer J. Clin. 71, 209–249 (2021).33538338
165. Thelen A Tumor-associated lymphangiogenesis correlates with prognosis after resection of human hepatocellular carcinoma Ann. Surg. Oncol. 2009 16 1222 1230 19224279
Thelen, A. et al. Tumor-associated lymphangiogenesis correlates with prognosis after resection of human hepatocellular carcinoma. Ann. Surg. Oncol. 16, 1222–1230 (2009).19224279
166. Thelen A VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma Int. J. Cancer 2008 122 2471 2481 18338756
Thelen, A. et al. VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma. Int. J. Cancer 122, 2471–2481 (2008).18338756
167. Shi Y HANR promotes lymphangiogenesis of hepatocellular carcinoma via secreting miR-296 exosome and regulating EAG1/VEGFA signaling in HDLEC cells J. Cell. Biochem. 2019 120 17699 17708 31127654
Shi, Y. et al. HANR promotes lymphangiogenesis of hepatocellular carcinoma via secreting miR-296 exosome and regulating EAG1/VEGFA signaling in HDLEC cells. J. Cell. Biochem. 120, 17699–17708 (2019).31127654
168. Zhang D Suppression of tumor growth and metastasis by simultaneously blocking vascular endothelial growth factor (VEGF)-A and VEGF-C with a receptor-immunoglobulin fusion protein Cancer Res. 2010 70 2495 2503 20197464
Zhang, D. et al. Suppression of tumor growth and metastasis by simultaneously blocking vascular endothelial growth factor (VEGF)-A and VEGF-C with a receptor-immunoglobulin fusion protein. Cancer Res. 70, 2495–2503 (2010).20197464
169. Brindley PJ Cholangiocarcinoma Nat. Rev. Dis. Prim. 2021 7 65 34504109
Brindley, P. J. et al. Cholangiocarcinoma. Nat. Rev. Dis. Prim. 7, 65 (2021).34504109
170. Sha M Tumor-associated lymphangiogenesis predicts unfavorable prognosis of intrahepatic cholangiocarcinoma BMC Cancer 2019 19 208 30849953
Sha, M. et al. Tumor-associated lymphangiogenesis predicts unfavorable prognosis of intrahepatic cholangiocarcinoma. BMC Cancer 19, 208 (2019).30849953
171. Carpino G Thrombospondin 1 and 2 along with PEDF inhibit angiogenesis and promote lymphangiogenesis in intrahepatic cholangiocarcinoma J. Hepatol. 2021 75 1377 1386 34329660
Carpino, G. et al. Thrombospondin 1 and 2 along with PEDF inhibit angiogenesis and promote lymphangiogenesis in intrahepatic cholangiocarcinoma. J. Hepatol. 75, 1377–1386 (2021).34329660
172. Cadamuro M Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma J. Hepatol. 2019 70 700 709 30553841
Cadamuro, M. et al. Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma. J. Hepatol. 70, 700–709 (2019).30553841
173. Yan, J. et al. Cancer-associated fibroblasts promote lymphatic metastasis in cholangiocarcinoma via the PDGF-BB/PDGFR-β mediated paracrine signaling network. Aging Dis. 14, 6 (2023).
174. Hezel AF Genetics and biology of pancreatic ductal adenocarcinoma Genes Dev. 2006 20 1218 1249 16702400
Hezel, A. F. et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20, 1218–1249 (2006).16702400
175. Hao S BANCR positively regulates the HIF-1α/VEGF-C/VEGFR-3 pathway in a hypoxic microenvironment to promote lymphangiogenesis in pancreatic cancer cells Oncol. Lett. 2022 24 422 36284647
Hao, S. et al. BANCR positively regulates the HIF-1α/VEGF-C/VEGFR-3 pathway in a hypoxic microenvironment to promote lymphangiogenesis in pancreatic cancer cells. Oncol. Lett. 24, 422 (2022).36284647
176. Kong Y circNFIB1 inhibits lymphangiogenesis and lymphatic metastasis via the miR-486-5p/PIK3R1/VEGF-C axis in pancreatic cancer Mol. Cancer 2020 19 82 32366257
Kong, Y. et al. circNFIB1 inhibits lymphangiogenesis and lymphatic metastasis via the miR-486-5p/PIK3R1/VEGF-C axis in pancreatic cancer. Mol. Cancer 19, 82 (2020).32366257
177. Wang CA DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination J. Extracell. Vesicles 2020 9 1746529 32341770
Wang, C. A. et al. DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination. J. Extracell. Vesicles 9, 1746529 (2020).32341770
178. Wang CA Suppression of extracellular vesicle VEGF-C-mediated lymphangiogenesis and pancreatic cancer early dissemination by a selective HDAC1/2 inhibitor Mol. Cancer Ther. 2021 20 1550 1560 34210825
Wang, C. A. et al. Suppression of extracellular vesicle VEGF-C-mediated lymphangiogenesis and pancreatic cancer early dissemination by a selective HDAC1/2 inhibitor. Mol. Cancer Ther. 20, 1550–1560 (2021).34210825
179. Luo Y KRAS mutant-driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer J. Clin. Investig. 2022 132 e157644 35579947
Luo, Y. et al. KRAS mutant-driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer. J. Clin. Investig. 132, e157644 (2022).35579947
180. Zhou X Pancreatic cancer cell-derived exosomes promote lymphangiogenesis by downregulating ABHD11-AS1 expression Cancers 2022 14 4612 36230535
Zhou, X. et al. Pancreatic cancer cell-derived exosomes promote lymphangiogenesis by downregulating ABHD11-AS1 expression. Cancers 14, 4612 (2022).36230535
181. Shen CN Lymphatic vessel remodeling and invasion in pancreatic cancer progression EBioMedicine 2019 47 98 113 31495721
Shen, C. N. et al. Lymphatic vessel remodeling and invasion in pancreatic cancer progression. EBioMedicine 47, 98–113 (2019).31495721
182. Pak KH Park KC Cheong JH VEGF-C induced by TGF- β1 signaling in gastric cancer enhances tumor-induced lymphangiogenesis BMC Cancer 2019 19 799 31409309
Pak, K. H., Park, K. C. & Cheong, J. H. VEGF-C induced by TGF- β1 signaling in gastric cancer enhances tumor-induced lymphangiogenesis. BMC Cancer 19, 799 (2019).31409309
183. Sun L Metastasis-associated in colon cancer-1 upregulates vascular endothelial growth factor-C/D to promote lymphangiogenesis in human gastric cancer Cancer Lett. 2015 357 242 253 25444928
Sun, L. et al. Metastasis-associated in colon cancer-1 upregulates vascular endothelial growth factor-C/D to promote lymphangiogenesis in human gastric cancer. Cancer Lett. 357, 242–253 (2015).25444928
184. Wu Z CRIP1 reshapes the gastric cancer microenvironment to facilitate development of lymphatic metastasis Adv. Sci. 2023 10 e2303246
Wu, Z. et al. CRIP1 reshapes the gastric cancer microenvironment to facilitate development of lymphatic metastasis. Adv. Sci. 10, e2303246 (2023).
185. Ma C OxLDL promotes lymphangiogenesis and lymphatic metastasis in gastric cancer by upregulating VEGF‑C expression and secretion Int. J. Oncol. 2019 54 572 584 30483757
Ma, C. et al. OxLDL promotes lymphangiogenesis and lymphatic metastasis in gastric cancer by upregulating VEGF‑C expression and secretion. Int. J. Oncol. 54, 572–584 (2019).30483757
186. Zhu T SOAT1 promotes gastric cancer lymph node metastasis through lipid synthesis Front. Pharmacol. 2021 12 769647 34790132
Zhu, T. et al. SOAT1 promotes gastric cancer lymph node metastasis through lipid synthesis. Front. Pharmacol. 12, 769647 (2021).34790132
187. Ma C Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion Gastric Cancer 2018 21 617 631 29243194
Ma, C. et al. Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion. Gastric Cancer 21, 617–631 (2018).29243194
188. Li H Anthracycline chemicals with anthracyclinone structure exert antitumor effects by inhibiting angiogenesis and lymphangiogenesis in a xenografted gastric tumor model Gastric Cancer 2023 26 863 877 37344705
Li, H. et al. Anthracycline chemicals with anthracyclinone structure exert antitumor effects by inhibiting angiogenesis and lymphangiogenesis in a xenografted gastric tumor model. Gastric Cancer 26, 863–877 (2023).37344705
189. Da W Zhang J Zhang R Zhu J Curcumin inhibits the lymphangiogenesis of gastric cancer cells by inhibiton of HMGB1/VEGF-D signaling Int. J. Immunopathol. Pharmacol. 2019 33 2058738419861600 31266378
Da, W., Zhang, J., Zhang, R. & Zhu, J. Curcumin inhibits the lymphangiogenesis of gastric cancer cells by inhibiton of HMGB1/VEGF-D signaling. Int. J. Immunopathol. Pharmacol. 33, 2058738419861600 (2019).31266378
190. Guan J Babao Dan inhibits lymphangiogenesis of gastric cancer in vitro and in vivo via lncRNA-ANRIL/VEGF-C/VEGFR-3 signaling axis Biomed. Pharmacother. 2022 154 113630 36058147
Guan, J. et al. Babao Dan inhibits lymphangiogenesis of gastric cancer in vitro and in vivo via lncRNA-ANRIL/VEGF-C/VEGFR-3 signaling axis. Biomed. Pharmacother. 154, 113630 (2022).36058147
191. Huang C Chen Y Lymphangiogenesis and colorectal cancer Saudi Med. J. 2017 38 237 244 28251217
Huang, C. & Chen, Y. Lymphangiogenesis and colorectal cancer. Saudi Med. J. 38, 237–244 (2017).28251217
192. Du B Metastasis-associated protein 1 induces VEGF-C and facilitates lymphangiogenesis in colorectal cancer World J. Gastroenterol. 2011 17 1219 1226, 21448429
Du, B. et al. Metastasis-associated protein 1 induces VEGF-C and facilitates lymphangiogenesis in colorectal cancer. World J. Gastroenterol. 17, 1219–1226, (2011).21448429
193. Sun B Colorectal cancer exosomes induce lymphatic network remodeling in lymph nodes Int. J. Cancer 2019 145 1648 1659 30734278
Sun, B. et al. Colorectal cancer exosomes induce lymphatic network remodeling in lymph nodes. Int. J. Cancer 145, 1648–1659 (2019).30734278
194. Song J CCBE1 promotes tumor lymphangiogenesis and is negatively regulated by TGFβ signaling in colorectal cancer Theranostics 2020 10 2327 2341 32089745
Song, J. et al. CCBE1 promotes tumor lymphangiogenesis and is negatively regulated by TGFβ signaling in colorectal cancer. Theranostics 10, 2327–2341 (2020).32089745
195. Huang B Qingjie Fuzheng Granule suppresses lymphangiogenesis in colorectal cancer via the VEGF-C/VEGFR-3 dependent PI3K/AKT pathway Biomed. Pharmacother. 2021 137 111331 33578235
Huang, B. et al. Qingjie Fuzheng Granule suppresses lymphangiogenesis in colorectal cancer via the VEGF-C/VEGFR-3 dependent PI3K/AKT pathway. Biomed. Pharmacother. 137, 111331 (2021).33578235
196. Huang B ANRIL promotes the regulation of colorectal cancer on lymphatic endothelial cells via VEGF-C and is the key target for Pien Tze Huang to inhibit cancer metastasis Cancer Gene Ther. 2023 30 1260 1273 37286729
Huang, B. et al. ANRIL promotes the regulation of colorectal cancer on lymphatic endothelial cells via VEGF-C and is the key target for Pien Tze Huang to inhibit cancer metastasis. Cancer Gene Ther. 30, 1260–1273 (2023).37286729
197. Li H Hedyotis diffusa Willd. inhibits VEGF‑C‑mediated lymphangiogenesis in colorectal cancer via multiple signaling pathways Oncol. Rep. 2019 42 1225 1236 31322263
Li, H. et al. Hedyotis diffusa Willd. inhibits VEGF‑C‑mediated lymphangiogenesis in colorectal cancer via multiple signaling pathways. Oncol. Rep. 42, 1225–1236 (2019).31322263
198. Miyata Y Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and -D Clin. Cancer Res. 2006 12 800 806 16467091
Miyata, Y. et al. Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and -D. Clin. Cancer Res. 12, 800–806 (2006).16467091
199. Chen C LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment Nat. Commun. 2018 9 3826 30237493
Chen, C. et al. LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment. Nat. Commun. 9, 3826 (2018).30237493
200. Chen C Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer J. Clin. Investig. 2020 130 404 421 31593555
Chen, C. et al. Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer. J. Clin. Investig. 130, 404–421 (2020).31593555
201. Chen C SUMOylation promotes extracellular vesicle-mediated transmission of lncRNA ELNAT1 and lymph node metastasis in bladder cancer J. Clin. Investig. 2021 131 e146431 33661764
Chen, C. et al. SUMOylation promotes extracellular vesicle-mediated transmission of lncRNA ELNAT1 and lymph node metastasis in bladder cancer. J. Clin. Investig. 131, e146431 (2021).33661764
202. He W Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis J. Clin. Investig. 2018 128 861 875 29355840
He, W. et al. Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. J. Clin. Investig. 128, 861–875 (2018).29355840
203. Zhu J circEHBP1 promotes lymphangiogenesis and lymphatic metastasis of bladder cancer via miR-130a-3p/TGFβR1/VEGF-D signaling Mol. Ther. 2021 29 1838 1852 33545359
Zhu, J. et al. circEHBP1 promotes lymphangiogenesis and lymphatic metastasis of bladder cancer via miR-130a-3p/TGFβR1/VEGF-D signaling. Mol. Ther. 29, 1838–1852 (2021).33545359
204. Yang H Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer Mol. Cancer 2011 10 36 21481239
Yang, H. et al. Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer. Mol. Cancer 10, 36 (2011).21481239
205. Zeng Y Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer Clin. Cancer Res. 2004 10 5137 5144 15297417
Zeng, Y. et al. Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer. Clin. Cancer Res. 10, 5137–5144 (2004).15297417
206. Lin YC LPA(1/3) signaling mediates tumor lymphangiogenesis through promoting CRT expression in prostate cancer Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2018 1863 1305 1315 30053596
Lin, Y. C. et al. LPA(1/3) signaling mediates tumor lymphangiogenesis through promoting CRT expression in prostate cancer. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1863, 1305–1315 (2018).30053596
207. Burton JB Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis Cancer Res. 2008 68 7828 7837 18829538
Burton, J. B. et al. Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res. 68, 7828–7837 (2008).18829538
208. Yano A Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells Clin. Cancer Res. 2006 12 6012 6017 17062674
Yano, A. et al. Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells. Clin. Cancer Res. 12, 6012–6017 (2006).17062674
209. Sopo M Microvessels in epithelial ovarian tumors: high microvessel density is a significant feature of malignant ovarian tumors Anticancer Res. 2020 40 6923 6931 33288586
Sopo, M. et al. Microvessels in epithelial ovarian tumors: high microvessel density is a significant feature of malignant ovarian tumors. Anticancer Res. 40, 6923–6931 (2020).33288586
210. Sapoznik S Gonadotropin-regulated lymphangiogenesis in ovarian cancer is mediated by LEDGF-induced expression of VEGF-C Cancer Res. 2009 69 9306 9314 19934313
Sapoznik, S. et al. Gonadotropin-regulated lymphangiogenesis in ovarian cancer is mediated by LEDGF-induced expression of VEGF-C. Cancer Res. 69, 9306–9314 (2009).19934313
211. Hsieh CY Overexpression of Her-2/NEU in epithelial ovarian carcinoma induces vascular endothelial growth factor C by activating NF-kappa B: implications for malignant ascites formation and tumor lymphangiogenesis J. Biomed. Sci. 2004 11 249 259 14966375
Hsieh, C. Y. et al. Overexpression of Her-2/NEU in epithelial ovarian carcinoma induces vascular endothelial growth factor C by activating NF-kappa B: implications for malignant ascites formation and tumor lymphangiogenesis. J. Biomed. Sci. 11, 249–259 (2004).14966375
212. Sun R ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer Theranostics 2023 13 833 848 36632222
Sun, R. et al. ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer. Theranostics 13, 833–848 (2023).36632222
213. Peng F SPARC suppresses lymph node metastasis by regulating the expression of VEGFs in ovarian carcinoma Int. J. Oncol. 2017 51 1920 1928 29075785
Peng, F. et al. SPARC suppresses lymph node metastasis by regulating the expression of VEGFs in ovarian carcinoma. Int. J. Oncol. 51, 1920–1928 (2017).29075785
214. Chen X Tumor necrosis factor-α promotes the tumorigenesis, lymphangiogenesis, and lymphatic metastasis in cervical cancer via activating VEGFC-mediated AKT and ERK pathways Mediators Inflamm. 2023 2023 5679966 37124061
Chen, X. et al. Tumor necrosis factor-α promotes the tumorigenesis, lymphangiogenesis, and lymphatic metastasis in cervical cancer via activating VEGFC-mediated AKT and ERK pathways. Mediators Inflamm. 2023, 5679966 (2023).37124061
215. Liu P High expression of PTPRM predicts poor prognosis and promotes tumor growth and lymph node metastasis in cervical cancer Cell Death Dis. 2020 11 687 32826853
Liu, P. et al. High expression of PTPRM predicts poor prognosis and promotes tumor growth and lymph node metastasis in cervical cancer. Cell Death Dis. 11, 687 (2020).32826853
216. Du Q FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis Cell Death Dis. 2022 13 488 35597782
Du, Q. et al. FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis. Cell Death Dis. 13, 488 (2022).35597782
217. Zhang C FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism Theranostics 2020 10 6561 6580 32550890
Zhang, C. et al. FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism. Theranostics 10, 6561–6580 (2020).32550890
218. Zhou CF Cervical squamous cell carcinoma-secreted exosomal miR-221-3p promotes lymphangiogenesis and lymphatic metastasis by targeting VASH1 Oncogene 2019 38 1256 1268 30254211
Zhou, C. F. et al. Cervical squamous cell carcinoma-secreted exosomal miR-221-3p promotes lymphangiogenesis and lymphatic metastasis by targeting VASH1. Oncogene 38, 1256–1268 (2019).30254211
219. Zhang C CircVPRBP inhibits nodal metastasis of cervical cancer by impeding RACK1 O-GlcNAcylation and stability Oncogene 2023 42 793 807 36658304
Zhang, C. et al. CircVPRBP inhibits nodal metastasis of cervical cancer by impeding RACK1 O-GlcNAcylation and stability. Oncogene 42, 793–807 (2023).36658304
220. Choi Y Papillary thyroid carcinoma involving cervical neck lymph nodes: correlations with lymphangiogenesis and ultrasound features Endocr. J. 2012 59 941 948 22785182
Choi, Y. et al. Papillary thyroid carcinoma involving cervical neck lymph nodes: correlations with lymphangiogenesis and ultrasound features. Endocr. J. 59, 941–948 (2012).22785182
221. Hakala T Recurrent thyroid cancers have more peritumoural lymphatic vasculature than nonrecurrent thyroid cancers Eur. J. Clin. Investig. 2014 44 825 832 25047155
Hakala, T. et al. Recurrent thyroid cancers have more peritumoural lymphatic vasculature than nonrecurrent thyroid cancers. Eur. J. Clin. Investig. 44, 825–832 (2014).25047155
222. Liu X Long non-coding RNA MFSD4A-AS1 promotes lymphangiogenesis and lymphatic metastasis of papillary thyroid cancer Endocr. Relat. Cancer 2023 30 e220221 36606578
Liu, X. et al. Long non-coding RNA MFSD4A-AS1 promotes lymphangiogenesis and lymphatic metastasis of papillary thyroid cancer. Endocr. Relat. Cancer 30, e220221 (2023).36606578
223. Špirić Z Vještica M Erić M Survival prediction in patients with cutaneous melanoma by tumour lymphangiogenesis Acta Clin. Belg. 2020 75 379 387 31210586
Špirić, Z., Vještica, M. & Erić, M. Survival prediction in patients with cutaneous melanoma by tumour lymphangiogenesis. Acta Clin. Belg. 75, 379–387 (2020).31210586
224. Leichner GS Primary Melanoma miRNA Trafficking Induces Lymphangiogenesis J. Investig. Dermatol. 2023 143 1788 1798.e1787 36934839
Leichner, G. S. et al. Primary Melanoma miRNA Trafficking Induces Lymphangiogenesis. J. Investig. Dermatol. 143, 1788–1798.e1787 (2023).36934839
225. García-Silva S Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism Nat. Cancer 2021 2 1387 1405 34957415
García-Silva, S. et al. Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism. Nat. Cancer 2, 1387–1405 (2021).34957415
226. Reger de Moura C CD147 promotes tumor lymphangiogenesis in melanoma via PROX-1 Cancers 2021 13 4859 34638342
Reger de Moura, C. et al. CD147 promotes tumor lymphangiogenesis in melanoma via PROX-1. Cancers 13, 4859 (2021).34638342
227. Benyahia Z Adrenomedullin secreted by melanoma cells promotes melanoma tumor growth through angiogenesis and lymphangiogenesis Cancers 2022 14 5909 36497391
Benyahia, Z. et al. Adrenomedullin secreted by melanoma cells promotes melanoma tumor growth through angiogenesis and lymphangiogenesis. Cancers 14, 5909 (2022).36497391
228. Berta J Apelin promotes blood and lymph vessel formation and the growth of melanoma lung metastasis Sci. Rep. 2021 11 5798 33707612
Berta, J. et al. Apelin promotes blood and lymph vessel formation and the growth of melanoma lung metastasis. Sci. Rep. 11, 5798 (2021).33707612
229. Lei N Claudin-3 inhibits tumor-induced lymphangiogenesis via regulating the PI3K signaling pathway in lymphatic endothelial cells Sci. Rep. 2022 12 17440 36261482
Lei, N. et al. Claudin-3 inhibits tumor-induced lymphangiogenesis via regulating the PI3K signaling pathway in lymphatic endothelial cells. Sci. Rep. 12, 17440 (2022).36261482
230. Wang M Rapamycin suppresses angiogenesis and lymphangiogenesis in melanoma by downregulating VEGF-A/VEGFR-2 and VEGF-C/VEGFR-3 expression OncoTargets Ther. 2019 12 4643 4654
Wang, M. et al. Rapamycin suppresses angiogenesis and lymphangiogenesis in melanoma by downregulating VEGF-A/VEGFR-2 and VEGF-C/VEGFR-3 expression. OncoTargets Ther. 12, 4643–4654 (2019).
231. Hsu MJ Anti-angiogenetic and anti-lymphangiogenic effects of a novel 2-aminobenzimidazole derivative, MFB Front. Oncol. 2022 12 862326 35795066
Hsu, M. J. et al. Anti-angiogenetic and anti-lymphangiogenic effects of a novel 2-aminobenzimidazole derivative, MFB. Front. Oncol. 12, 862326 (2022).35795066
232. Sasso MS Lymphangiogenesis-inducing vaccines elicit potent and long-lasting T cell immunity against melanomas Sci. Adv. 2021 7 eabe4362 33762337
Sasso, M. S. et al. Lymphangiogenesis-inducing vaccines elicit potent and long-lasting T cell immunity against melanomas. Sci. Adv. 7, eabe4362 (2021).33762337
233. Mawuenyega KG Decreased clearance of CNS beta-amyloid in Alzheimer’s disease Science 2010 330 1774 21148344
Mawuenyega, K. G. et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330, 1774 (2010).21148344
234. Da Mesquita S Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease Nature 2018 560 185 191 30046111
Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185–191 (2018).30046111
235. Wen YR Yang JH Wang X Yao ZB Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer’s disease Neural Regen. Res. 2018 13 709 716 29722325
Wen, Y. R., Yang, J. H., Wang, X. & Yao, Z. B. Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer’s disease. Neural Regen. Res. 13, 709–716 (2018).29722325
236. Da Mesquita S Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy Nature 2021 593 255 260 33911285
Da Mesquita, S. et al. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature 593, 255–260 (2021).33911285
237. Aspelund A The Schlemm’s canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel J. Clin. Investig. 2014 124 3975 3986 25061878
Aspelund, A. et al. The Schlemm’s canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel. J. Clin. Investig. 124, 3975–3986 (2014).25061878
238. Kim J Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma J. Clin. Investig. 2017 127 3877 3896 28920924
Kim, J. et al. Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma. J. Clin. Investig. 127, 3877–3896 (2017).28920924
239. Young TL SVEP1 as a genetic modifier of TEK-related primary congenital glaucoma Investig. Ophthalmol. Vis. Sci. 2020 61 6
Young, T. L. et al. SVEP1 as a genetic modifier of TEK-related primary congenital glaucoma. Investig. Ophthalmol. Vis. Sci. 61, 6 (2020).
240. Piché ME Tchernof A Després JP Obesity phenotypes, diabetes, and cardiovascular diseases Circ. Res. 2020 126 1477 1500 32437302
Piché, M. E., Tchernof, A. & Després, J. P. Obesity phenotypes, diabetes, and cardiovascular diseases. Circ. Res. 126, 1477–1500 (2020).32437302
241. Kojta I Chacińska M Błachnio-Zabielska A Obesity, bioactive lipids, and adipose tissue inflammation in insulin resistance Nutrients 2020 12 1305 32375231
Kojta, I., Chacińska, M. & Błachnio-Zabielska, A. Obesity, bioactive lipids, and adipose tissue inflammation in insulin resistance. Nutrients 12, 1305 (2020).32375231
242. Savetsky IL Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema Am. J. Physiol. Heart Circ. Physiol. 2014 307 H165 172, 24858842
Savetsky, I. L. et al. Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema. Am. J. Physiol. Heart Circ. Physiol. 307, H165–172, (2014).24858842
243. García Nores GD Obesity but not high-fat diet impairs lymphatic function Int. J. Obes. 2016 40 1582 1590
García Nores, G. D. et al. Obesity but not high-fat diet impairs lymphatic function. Int. J. Obes. 40, 1582–1590 (2016).
244. Chakraborty A Vascular endothelial growth factor-D (VEGF-D) overexpression and lymphatic expansion in murine adipose tissue improves metabolism in obesity Am. J. Pathol. 2019 189 924 939 30878136
Chakraborty, A. et al. Vascular endothelial growth factor-D (VEGF-D) overexpression and lymphatic expansion in murine adipose tissue improves metabolism in obesity. Am. J. Pathol. 189, 924–939 (2019).30878136
245. Chakraborty A Characterizing lymphangiogenesis and concurrent inflammation in adipose tissue in response to VEGF-D Front. Physiol. 2020 11 363 32390866
Chakraborty, A. et al. Characterizing lymphangiogenesis and concurrent inflammation in adipose tissue in response to VEGF-D. Front. Physiol. 11, 363 (2020).32390866
246. Amann-Vesti BR Franzeck UK Bollinger A Microlymphatic aneurysms in patients with lipedema Lymphology 2001 34 170 175 11783595
Amann-Vesti, B. R., Franzeck, U. K. & Bollinger, A. Microlymphatic aneurysms in patients with lipedema. Lymphology 34, 170–175 (2001).11783595
247. Lohrmann C Foeldi E Langer M MR imaging of the lymphatic system in patients with lipedema and lipo-lymphedema Microvasc. Res. 2009 77 335 339 19323976
Lohrmann, C., Foeldi, E. & Langer, M. MR imaging of the lymphatic system in patients with lipedema and lipo-lymphedema. Microvasc. Res. 77, 335–339 (2009).19323976
248. Harvey NL Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity Nat. Genet. 2005 37 1072 1081 16170315
Harvey, N. L. et al. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat. Genet. 37, 1072–1081 (2005).16170315
249. Blum KS Chronic high-fat diet impairs collecting lymphatic vessel function in mice PLoS One 2014 9 e94713 24714646
Blum, K. S. et al. Chronic high-fat diet impairs collecting lymphatic vessel function in mice. PLoS One 9, e94713 (2014).24714646
250. Silha JV Krsek M Sucharda P Murphy LJ Angiogenic factors are elevated in overweight and obese individuals Int. J. Obes. 2005 29 1308 1314
Silha, J. V., Krsek, M., Sucharda, P. & Murphy, L. J. Angiogenic factors are elevated in overweight and obese individuals. Int. J. Obes. 29, 1308–1314 (2005).
251. Demir S Nawroth PP Herzig S Ekim Üstünel B Emerging targets in type 2 diabetes and diabetic complications Adv. Sci. 2021 8 e2100275
Demir, S., Nawroth, P. P., Herzig, S. & Ekim Üstünel, B. Emerging targets in type 2 diabetes and diabetic complications. Adv. Sci. 8, e2100275 (2021).
252. Wenstedt EFE Salt-sensitive blood pressure rise in type 1 diabetes patients is accompanied by disturbed skin macrophage influx and lymphatic dilation—a proof-of-concept study Transl. Res. 2020 217 23 32 31883728
Wenstedt, E. F. E. et al. Salt-sensitive blood pressure rise in type 1 diabetes patients is accompanied by disturbed skin macrophage influx and lymphatic dilation—a proof-of-concept study. Transl. Res. 217, 23–32 (2020).31883728
253. Wu H Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes J. Clin. Investig. 2018 128 4025 4043 30102256
Wu, H. et al. Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes. J. Clin. Investig. 128, 4025–4043 (2018).30102256
254. Scallan JP Hill MA Davis MJ Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling Cardiovasc. Res. 2015 107 89 97 25852084
Scallan, J. P., Hill, M. A. & Davis, M. J. Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling. Cardiovasc. Res. 107, 89–97 (2015).25852084
255. Cifarelli V Visceral obesity and insulin resistance associate with CD36 deletion in lymphatic endothelial cells Nat. Commun. 2021 12 3350 34099721
Cifarelli, V. et al. Visceral obesity and insulin resistance associate with CD36 deletion in lymphatic endothelial cells. Nat. Commun. 12, 3350 (2021).34099721
256. Cole JB Florez JC Genetics of diabetes mellitus and diabetes complications Nat. Rev. Nephrol. 2020 16 377 390 32398868
Cole, J. B. & Florez, J. C. Genetics of diabetes mellitus and diabetes complications. Nat. Rev. Nephrol. 16, 377–390 (2020).32398868
257. Alicic RZ Rooney MT Tuttle KR Diabetic kidney disease: challenges, progress, and possibilities Clin. J. Am. Soc. Nephrol. 2017 12 2032 2045 28522654
Alicic, R. Z., Rooney, M. T. & Tuttle, K. R. Diabetic kidney disease: challenges, progress, and possibilities. Clin. J. Am. Soc. Nephrol. 12, 2032–2045 (2017).28522654
258. Kim Y Attenuated lymphatic proliferation ameliorates diabetic nephropathy and high-fat diet-induced renal lipotoxicity Sci. Rep. 2019 9 1994 30760777
Kim, Y. et al. Attenuated lymphatic proliferation ameliorates diabetic nephropathy and high-fat diet-induced renal lipotoxicity. Sci. Rep. 9, 1994 (2019).30760777
259. Sakamoto I Lymphatic vessels develop during tubulointerstitial fibrosis Kidney Int. 2009 75 828 838 19145238
Sakamoto, I. et al. Lymphatic vessels develop during tubulointerstitial fibrosis. Kidney Int. 75, 828–838 (2009).19145238
260. Hwang SD Inhibition of lymphatic proliferation by the selective VEGFR-3 inhibitor SAR131675 ameliorates diabetic nephropathy in db/db mice Cell Death Dis. 2019 10 219 30833548
Hwang, S. D. et al. Inhibition of lymphatic proliferation by the selective VEGFR-3 inhibitor SAR131675 ameliorates diabetic nephropathy in db/db mice. Cell Death Dis. 10, 219 (2019).30833548
261. Cheung N Mitchell P Wong TY Diabetic retinopathy Lancet 2010 376 124 136 20580421
Cheung, N., Mitchell, P. & Wong, T. Y. Diabetic retinopathy. Lancet 376, 124–136 (2010).20580421
262. Gucciardo E Loukovaara S Salven P Lehti K Lymphatic vascular structures: a new aspect in proliferative diabetic retinopathy Int. J. Mol. Sci. 2018 19 4034 30551619
Gucciardo, E., Loukovaara, S., Salven, P. & Lehti, K. Lymphatic vascular structures: a new aspect in proliferative diabetic retinopathy. Int. J. Mol. Sci. 19, 4034 (2018).30551619
263. Kim BH Imidazole-based alkaloid derivative LCB54-0009 suppresses ocular angiogenesis and lymphangiogenesis in models of experimental retinopathy and corneal neovascularization Br. J. Pharmacol. 2015 172 3875 3889 25917462
Kim, B. H. et al. Imidazole-based alkaloid derivative LCB54-0009 suppresses ocular angiogenesis and lymphangiogenesis in models of experimental retinopathy and corneal neovascularization. Br. J. Pharmacol. 172, 3875–3889 (2015).25917462
264. Gucciardo E The microenvironment of proliferative diabetic retinopathy supports lymphatic neovascularization J. Pathol. 2018 245 172 185 29536540
Gucciardo, E. et al. The microenvironment of proliferative diabetic retinopathy supports lymphatic neovascularization. J. Pathol. 245, 172–185 (2018).29536540
265. Korhonen A Gucciardo E Lehti K Loukovaara S Proliferative diabetic retinopathy transcriptomes reveal angiogenesis, anti-angiogenic therapy escape mechanisms, fibrosis and lymphatic involvement Sci. Rep. 2021 11 18810 34552123
Korhonen, A., Gucciardo, E., Lehti, K. & Loukovaara, S. Proliferative diabetic retinopathy transcriptomes reveal angiogenesis, anti-angiogenic therapy escape mechanisms, fibrosis and lymphatic involvement. Sci. Rep. 11, 18810 (2021).34552123
266. Renò F Sabbatini M Breaking a vicious circle: lymphangiogenesis as a new therapeutic target in wound healing Biomedicines 2023 11 656 36979635
Renò, F. & Sabbatini, M. Breaking a vicious circle: lymphangiogenesis as a new therapeutic target in wound healing. Biomedicines 11, 656 (2023).36979635
267. Cho CH COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model Proc. Natl Acad. Sci. USA 2006 103 4946 4951 16543381
Cho, C. H. et al. COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model. Proc. Natl Acad. Sci. USA 103, 4946–4951 (2006).16543381
268. Zhou J Wei T He Z ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m(6)A modification to improve wound healing of diabetic foot ulcers Mol. Med. 2021 27 146 34773968
Zhou, J., Wei, T. & He, Z. ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m(6)A modification to improve wound healing of diabetic foot ulcers. Mol. Med. 27, 146 (2021).34773968
269. Wu M Modulation of lymphangiogenesis in incisional murine diabetic wound healing using negative pressure wound therapy Adv. Wound Care 2023 12 483 497
Wu, M. et al. Modulation of lymphangiogenesis in incisional murine diabetic wound healing using negative pressure wound therapy. Adv. Wound Care 12, 483–497 (2023).
270. Wu M Negative-pressure wound therapy induces lymphangiogenesis in murine diabetic wound healing Plast. Reconstr. Surg. 2023 151 779 790 36729939
Wu, M. et al. Negative-pressure wound therapy induces lymphangiogenesis in murine diabetic wound healing. Plast. Reconstr. Surg. 151, 779–790 (2023).36729939
271. Asai J Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis Am. J. Pathol. 2012 181 2217 2224 23138019
Asai, J. et al. Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis. Am. J. Pathol. 181, 2217–2224 (2012).23138019
272. He ZY Long noncoding RNA-antisense noncoding RNA in the INK4 locus accelerates wound healing in diabetes by promoting lymphangiogenesis via regulating miR-181a/Prox1 axis J. Cell Physiol. 2019 234 4627 4640 30565672
He, Z. Y. et al. Long noncoding RNA-antisense noncoding RNA in the INK4 locus accelerates wound healing in diabetes by promoting lymphangiogenesis via regulating miR-181a/Prox1 axis. J. Cell Physiol. 234, 4627–4640 (2019).30565672
273. He ZY Long noncoding RNA GAS5 accelerates diabetic wound healing and promotes lymphangiogenesis via miR-217/Prox1 axis Mol. Cell Endocrinol. 2021 532 111283 33865922
He, Z. Y. et al. Long noncoding RNA GAS5 accelerates diabetic wound healing and promotes lymphangiogenesis via miR-217/Prox1 axis. Mol. Cell Endocrinol. 532, 111283 (2021).33865922
274. Güç E Local induction of lymphangiogenesis with engineered fibrin-binding VEGF-C promotes wound healing by increasing immune cell trafficking and matrix remodeling Biomaterials 2017 131 160 175 28410495
Güç, E. et al. Local induction of lymphangiogenesis with engineered fibrin-binding VEGF-C promotes wound healing by increasing immune cell trafficking and matrix remodeling. Biomaterials 131, 160–175 (2017).28410495
275. Eming SA Martin P Tomic-Canic M Wound repair and regeneration: mechanisms, signaling, and translation Sci. Transl. Med. 2014 6 265sr266
Eming, S. A., Martin, P. & Tomic-Canic, M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci. Transl. Med. 6, 265sr266 (2014).
276. Brunner LM Promotion of lymphangiogenesis by targeted delivery of VEGF-C improves diabetic wound healing Cells 2023 12 472 36766814
Brunner, L. M. et al. Promotion of lymphangiogenesis by targeted delivery of VEGF-C improves diabetic wound healing. Cells 12, 472 (2023).36766814
277. Lim L Hemostasis stimulates lymphangiogenesis through release and activation of VEGFC Blood 2019 134 1764 1775 31562136
Lim, L. et al. Hemostasis stimulates lymphangiogenesis through release and activation of VEGFC. Blood 134, 1764–1775 (2019).31562136
278. Zampell JC HIF-1α coordinates lymphangiogenesis during wound healing and in response to inflammation FASEB J. 2012 26 1027 1039 22067482
Zampell, J. C. et al. HIF-1α coordinates lymphangiogenesis during wound healing and in response to inflammation. FASEB J. 26, 1027–1039 (2012).22067482
279. Hosono K Signaling of prostaglandin E receptors, EP3 and EP4 facilitates wound healing and lymphangiogenesis with enhanced recruitment of M2 macrophages in mice PLoS One 2016 11 e0162532 27711210
Hosono, K. et al. Signaling of prostaglandin E receptors, EP3 and EP4 facilitates wound healing and lymphangiogenesis with enhanced recruitment of M2 macrophages in mice. PLoS One 11, e0162532 (2016).27711210
280. Bianchi A Painter KJ Sherratt JA Spatio-temporal models of lymphangiogenesis in wound healing Bull. Math. Biol. 2016 78 1904 1941 27670430
Bianchi, A., Painter, K. J. & Sherratt, J. A. Spatio-temporal models of lymphangiogenesis in wound healing. Bull. Math. Biol. 78, 1904–1941 (2016).27670430
281. Gur-Cohen S Stem cell-driven lymphatic remodeling coordinates tissue regeneration Science 2019 366 1218 1225 31672914
Gur-Cohen, S. et al. Stem cell-driven lymphatic remodeling coordinates tissue regeneration. Science 366, 1218–1225 (2019).31672914
282. Peña-Jimenez D Lymphatic vessels interact dynamically with the hair follicle stem cell niche during skin regeneration in vivo EMBO J. 2019 38 e101688 31475747
Peña-Jimenez, D. et al. Lymphatic vessels interact dynamically with the hair follicle stem cell niche during skin regeneration in vivo. EMBO J. 38, e101688 (2019).31475747
283. Biswas L Lymphatic vessels in bone support regeneration after injury Cell 2023 186 382 397.e24 36669473
Biswas, L. et al. Lymphatic vessels in bone support regeneration after injury. Cell 186, 382–397.e24 (2023).36669473
284. Gancz D Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration Elife 2019 8 e44153 31702554
Gancz, D. et al. Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration. Elife 8, e44153 (2019).31702554
285. Trincot CE Adrenomedullin induces cardiac lymphangiogenesis after myocardial infarction and regulates cardiac edema via connexin 43 Circ. Res. 2019 124 101 113 30582443
Trincot, C. E. et al. Adrenomedullin induces cardiac lymphangiogenesis after myocardial infarction and regulates cardiac edema via connexin 43. Circ. Res. 124, 101–113 (2019).30582443
286. Mo F Mamonkin M Brenner MK Heslop HE Taking T-cell oncotherapy off-the-shelf Trends Immunol. 2021 42 261 272 33536140
Mo, F., Mamonkin, M., Brenner, M. K. & Heslop, H. E. Taking T-cell oncotherapy off-the-shelf. Trends Immunol. 42, 261–272 (2021).33536140
287. Wong BW Lymphatic vessels in solid organ transplantation and immunobiology Am. J. Transplant. 2020 20 1992 2000 32027464
Wong, B. W. Lymphatic vessels in solid organ transplantation and immunobiology. Am. J. Transplant. 20, 1992–2000 (2020).32027464
288. Dashkevich A Ischemia-reperfusion injury enhances lymphatic endothelial VEGFR3 and rejection in cardiac allografts Am. J. Transplant. 2016 16 1160 1172 26689983
Dashkevich, A. et al. Ischemia-reperfusion injury enhances lymphatic endothelial VEGFR3 and rejection in cardiac allografts. Am. J. Transplant. 16, 1160–1172 (2016).26689983
289. Edwards LA Chronic rejection of cardiac allografts is associated with increased lymphatic flow and cellular trafficking Circulation 2018 137 488 503 28775077
Edwards, L. A. et al. Chronic rejection of cardiac allografts is associated with increased lymphatic flow and cellular trafficking. Circulation 137, 488–503 (2018).28775077
290. Nykänen AI Targeting lymphatic vessel activation and CCL21 production by vascular endothelial growth factor receptor-3 inhibition has novel immunomodulatory and antiarteriosclerotic effects in cardiac allografts Circulation 2010 121 1413 1422 20231530
Nykänen, A. I. et al. Targeting lymphatic vessel activation and CCL21 production by vascular endothelial growth factor receptor-3 inhibition has novel immunomodulatory and antiarteriosclerotic effects in cardiac allografts. Circulation 121, 1413–1422 (2010).20231530
291. Kerjaschki D Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates J. Am. Soc. Nephrol. 2004 15 603 612 14978162
Kerjaschki, D. et al. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J. Am. Soc. Nephrol. 15, 603–612 (2004).14978162
292. Todd JL Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity Am. J. Respir. Crit. Care Med. 2014 189 556 566 24471427
Todd, J. L. et al. Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity. Am. J. Respir. Crit. Care Med. 189, 556–566 (2014).24471427
293. Cui Y Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection J. Clin. Investig. 2015 125 4255 4268 26485284
Cui, Y. et al. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection. J. Clin. Investig. 125, 4255–4268 (2015).26485284
294. Pedersen MS Lymphangiogenesis in a mouse model of renal transplant rejection extends life span of the recipients Kidney Int. 2020 97 89 94 31718844
Pedersen, M. S. et al. Lymphangiogenesis in a mouse model of renal transplant rejection extends life span of the recipients. Kidney Int. 97, 89–94 (2020).31718844
295. Dertschnig S Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity J. Clin. Investig. 2020 130 1896 1911 31917684
Dertschnig, S. et al. Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity. J. Clin. Investig. 130, 1896–1911 (2020).31917684
296. Gehlsen U Ocular graft-versus-host disease in a chemotherapy-based minor-mismatch mouse model features corneal (Lymph-) angiogenesis Int. J. Mol. Sci. 2021 22 6191 34201218
Gehlsen, U. et al. Ocular graft-versus-host disease in a chemotherapy-based minor-mismatch mouse model features corneal (Lymph-) angiogenesis. Int. J. Mol. Sci. 22, 6191 (2021).34201218
297. Mertlitz S Lymphangiogenesis is a feature of acute GVHD, and VEGFR-3 inhibition protects against experimental GVHD Blood 2017 129 1865 1875 28096093
Mertlitz, S. et al. Lymphangiogenesis is a feature of acute GVHD, and VEGFR-3 inhibition protects against experimental GVHD. Blood 129, 1865–1875 (2017).28096093
298. Valtola R VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer Am. J. Pathol. 1999 154 1381 1390 10329591
Valtola, R. et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am. J. Pathol. 154, 1381–1390 (1999).10329591
299. Zhang Y Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-κB signaling and protects against endotoxin shock Immunity 2014 40 501 514 24656836
Zhang, Y. et al. Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-κB signaling and protects against endotoxin shock. Immunity 40, 501–514 (2014).24656836
300. Salameh A Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways Blood 2005 106 3423 3431 16076871
Salameh, A. et al. Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways. Blood 106, 3423–3431 (2005).16076871
301. Leppänen VM Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation Proc. Natl Acad. Sci. USA 2013 110 12960 12965 23878260
Leppänen, V. M. et al. Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proc. Natl Acad. Sci. USA 110, 12960–12965 (2013).23878260
302. Tan KW Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D Blood 2013 122 3666 3677 24113869
Tan, K. W. et al. Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D. Blood 122, 3666–3677 (2013).24113869
303. Wuest TR Carr DJ VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis J. Exp. Med. 2010 207 101 115 20026662
Wuest, T. R. & Carr, D. J. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. J. Exp. Med. 207, 101–115 (2010).20026662
304. Clatworthy MR Harford SK Mathews RJ Smith KG FcγRIIb inhibits immune complex-induced VEGF-A production and intranodal lymphangiogenesis Proc. Natl Acad. Sci. USA 2014 111 17971 17976 25475856
Clatworthy, M. R., Harford, S. K., Mathews, R. J. & Smith, K. G. FcγRIIb inhibits immune complex-induced VEGF-A production and intranodal lymphangiogenesis. Proc. Natl Acad. Sci. USA 111, 17971–17976 (2014).25475856
305. Liu PI ANGPTL2 promotes VEGF-A synthesis in human lung cancer and facilitates lymphangiogenesis Aging 2023 15 1652 1667 36917086
Liu, P. I. et al. ANGPTL2 promotes VEGF-A synthesis in human lung cancer and facilitates lymphangiogenesis. Aging 15, 1652–1667 (2023).36917086
306. Del Vecchio M Bevacizumab plus fotemustine as first-line treatment in metastatic melanoma patients: clinical activity and modulation of angiogenesis and lymphangiogenesis factors Clin. Cancer Res. 2010 16 5862 5872 21030496
Del Vecchio, M. et al. Bevacizumab plus fotemustine as first-line treatment in metastatic melanoma patients: clinical activity and modulation of angiogenesis and lymphangiogenesis factors. Clin. Cancer Res. 16, 5862–5872 (2010).21030496
307. Dumond A Anti-vascular endothelial growth factor C antibodies efficiently inhibit the growth of experimental clear cell renal cell carcinomas Cells 2021 10 1222 34067671
Dumond, A. et al. Anti-vascular endothelial growth factor C antibodies efficiently inhibit the growth of experimental clear cell renal cell carcinomas. Cells 10, 1222 (2021).34067671
308. Tampellini M Sonetto C Scagliotti GV Novel anti-angiogenic therapeutic strategies in colorectal cancer Expert. Opin. Investig. Drugs 2016 25 507 520 26938715
Tampellini, M., Sonetto, C. & Scagliotti, G. V. Novel anti-angiogenic therapeutic strategies in colorectal cancer. Expert. Opin. Investig. Drugs 25, 507–520 (2016).26938715
309. He Y Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling J. Natl Cancer Inst. 2002 94 819 825 12048269
He, Y. et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J. Natl Cancer Inst. 94, 819–825 (2002).12048269
310. Roberts N Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2 Cancer Res. 2006 66 2650 2657 16510584
Roberts, N. et al. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res. 66, 2650–2657 (2006).16510584
311. Zhu G Pazopanib inhibits tumor growth, lymph-node metastasis and lymphangiogenesis of an orthotopic mouse of colorectal cancer Cancer Genom. Proteom. 2020 17 131 139
Zhu, G. et al. Pazopanib inhibits tumor growth, lymph-node metastasis and lymphangiogenesis of an orthotopic mouse of colorectal cancer. Cancer Genom. Proteom. 17, 131–139 (2020).
312. Mäkinen T Norrmén C Petrova TV Molecular mechanisms of lymphatic vascular development Cell Mol. Life Sci. 2007 64 1915 1929 17458498
Mäkinen, T., Norrmén, C. & Petrova, T. V. Molecular mechanisms of lymphatic vascular development. Cell Mol. Life Sci. 64, 1915–1929 (2007).17458498
313. Detry B Sunitinib inhibits inflammatory corneal lymphangiogenesis Investig. Ophthalmol. Vis. Sci. 2013 54 3082 3093, 23580490
Detry, B. et al. Sunitinib inhibits inflammatory corneal lymphangiogenesis. Investig. Ophthalmol. Vis. Sci. 54, 3082–3093, (2013).23580490
314. Dufies M Sunitinib stimulates expression of VEGFC by tumor cells and promotes lymphangiogenesis in clear cell renal cell carcinomas Cancer Res. 2017 77 1212 1226 28087600
Dufies, M. et al. Sunitinib stimulates expression of VEGFC by tumor cells and promotes lymphangiogenesis in clear cell renal cell carcinomas. Cancer Res. 77, 1212–1226 (2017).28087600
315. Chen Z Down-regulation of vascular endothelial cell growth factor-C expression using small interfering RNA vectors in mammary tumors inhibits tumor lymphangiogenesis and spontaneous metastasis and enhances survival Cancer Res. 2005 65 9004 9011 16204074
Chen, Z. et al. Down-regulation of vascular endothelial cell growth factor-C expression using small interfering RNA vectors in mammary tumors inhibits tumor lymphangiogenesis and spontaneous metastasis and enhances survival. Cancer Res. 65, 9004–9011 (2005).16204074
316. Shibata MA Morimoto J Shibata E Otsuki Y Combination therapy with short interfering RNA vectors against VEGF-C and VEGF-A suppresses lymph node and lung metastasis in a mouse immunocompetent mammary cancer model Cancer Gene Ther. 2008 15 776 786 18654613
Shibata, M. A., Morimoto, J., Shibata, E. & Otsuki, Y. Combination therapy with short interfering RNA vectors against VEGF-C and VEGF-A suppresses lymph node and lung metastasis in a mouse immunocompetent mammary cancer model. Cancer Gene Ther. 15, 776–786 (2008).18654613
317. Wang J Fucoxanthin inhibits gastric cancer lymphangiogenesis and metastasis by regulating Ran expression Phytomedicine 2023 118 154926 37392675
Wang, J. et al. Fucoxanthin inhibits gastric cancer lymphangiogenesis and metastasis by regulating Ran expression. Phytomedicine 118, 154926 (2023).37392675
318. Prangsaengtong O Shikonin suppresses lymphangiogenesis via NF-κB/HIF-1α axis inhibition Biol. Pharm. Bull. 2018 41 1659 1666 30381665
Prangsaengtong, O. et al. Shikonin suppresses lymphangiogenesis via NF-κB/HIF-1α axis inhibition. Biol. Pharm. Bull. 41, 1659–1666 (2018).30381665
319. Wang W Sukamtoh E Xiao H Zhang G Curcumin inhibits lymphangiogenesis in vitro and in vivo Mol. Nutr. Food Res. 2015 59 2345 2354 26375757
Wang, W., Sukamtoh, E., Xiao, H. & Zhang, G. Curcumin inhibits lymphangiogenesis in vitro and in vivo. Mol. Nutr. Food Res. 59, 2345–2354 (2015).26375757
320. Wilhelm K FOXO1 couples metabolic activity and growth state in the vascular endothelium Nature 2016 529 216 220 26735015
Wilhelm, K. et al. FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature 529, 216–220 (2016).26735015
321. Fagiani E Lorentz P Kopfstein L Christofori G Angiopoietin-1 and -2 exert antagonistic functions in tumor angiogenesis, yet both induce lymphangiogenesis Cancer Res. 2011 71 5717 5727 21778249
Fagiani, E., Lorentz, P., Kopfstein, L. & Christofori, G. Angiopoietin-1 and -2 exert antagonistic functions in tumor angiogenesis, yet both induce lymphangiogenesis. Cancer Res. 71, 5717–5727 (2011).21778249
322. Korhonen EA Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression J. Clin. Investig. 2022 132 e155478 35763346
Korhonen, E. A. et al. Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression. J. Clin. Investig. 132, e155478 (2022).35763346
323. Akwii RG Angiopoietin-2-induced lymphatic endothelial cell migration drives lymphangiogenesis via the β1 integrin-RhoA-formin axis Angiogenesis 2022 25 373 396 35103877
Akwii, R. G. et al. Angiopoietin-2-induced lymphatic endothelial cell migration drives lymphangiogenesis via the β1 integrin-RhoA-formin axis. Angiogenesis 25, 373–396 (2022).35103877
324. Le CT Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation Am. J. Pathol. 2015 185 2949 2968 26348576
Le, C. T. et al. Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation. Am. J. Pathol. 185, 2949–2968 (2015).26348576
325. Zhang L Angiopoietin-2 blockade promotes survival of corneal transplants Investig. Ophthalmol. Vis. Sci. 2017 58 79 86, 28061513
Zhang, L. et al. Angiopoietin-2 blockade promotes survival of corneal transplants. Investig. Ophthalmol. Vis. Sci. 58, 79–86, (2017).28061513
326. Wilhelm SM Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity Int. J. Cancer 2011 129 245 255 21170960
Wilhelm, S. M. et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int. J. Cancer 129, 245–255 (2011).21170960
327. Takigawa H Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma Cancer Sci. 2016 107 601 608 26865419
Takigawa, H. et al. Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma. Cancer Sci. 107, 601–608 (2016).26865419
328. Tarab-Ravski D Delivery of therapeutic RNA to the bone marrow in multiple myeloma using CD38-targeted lipid nanoparticles Adv. Sci. 2023 10 e2301377
Tarab-Ravski, D. et al. Delivery of therapeutic RNA to the bone marrow in multiple myeloma using CD38-targeted lipid nanoparticles. Adv. Sci. 10, e2301377 (2023).
329. Yan Y Nanomedicines reprogram synovial macrophages by scavenging nitric oxide and silencing CA9 in progressive osteoarthritis Adv. Sci. 2023 10 e2207490
Yan, Y. et al. Nanomedicines reprogram synovial macrophages by scavenging nitric oxide and silencing CA9 in progressive osteoarthritis. Adv. Sci. 10, e2207490 (2023).
330. Yarden Y The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities Eur. J. Cancer 2001 37 S3 S8 11597398
Yarden, Y. The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur. J. Cancer 37, S3–S8 (2001).11597398
331. Bracher A Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis J. Investig. Dermatol. 2013 133 230 238 22951723
Bracher, A. et al. Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis. J. Investig. Dermatol. 133, 230–238 (2013).22951723
332. Cripps C Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer Curr. Oncol. 2010 17 37 48 20567625
Cripps, C. et al. Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer. Curr. Oncol. 17, 37–48 (2010).20567625
333. Pao W Chmielecki J Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer Nat. Rev. Cancer 2010 10 760 774 20966921
Pao, W. & Chmielecki, J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat. Rev. Cancer 10, 760–774 (2010).20966921
334. Gore J Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model Cancer Lett. 2016 379 143 153 27267807
Gore, J. et al. Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model. Cancer Lett. 379, 143–153 (2016).27267807
335. Cao R Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis Proc. Natl Acad. Sci. USA 2012 109 15894 15899 22967508
Cao, R. et al. Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proc. Natl Acad. Sci. USA 109, 15894–15899 (2012).22967508
336. Platonova N Evidence for the interaction of fibroblast growth factor-2 with the lymphatic endothelial cell marker LYVE-1 Blood 2013 121 1229 1237 23264596
Platonova, N. et al. Evidence for the interaction of fibroblast growth factor-2 with the lymphatic endothelial cell marker LYVE-1. Blood 121, 1229–1237 (2013).23264596
337. Cao R Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action Blood 2006 107 3531 3536 16424394
Cao, R. et al. Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. Blood 107, 3531–3536 (2006).16424394
338. Guérit E PDGF receptor mutations in human diseases Cell Mol. Life Sci. 2021 78 3867 3881 33449152
Guérit, E. et al. PDGF receptor mutations in human diseases. Cell Mol. Life Sci. 78, 3867–3881 (2021).33449152
339. Zou X Targeting the PDGF/PDGFR signaling pathway for cancer therapy: a review Int J. Biol. Macromol. 2022 202 539 557 35074329
Zou, X. et al. Targeting the PDGF/PDGFR signaling pathway for cancer therapy: a review. Int J. Biol. Macromol. 202, 539–557 (2022).35074329
340. Cao R PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis Cancer cell 2004 6 333 345 15488757
Cao, R. et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer cell 6, 333–345 (2004).15488757
341. Kerr A Baxter RC Noncoding RNA actions through IGFs and IGF binding proteins in cancer Oncogene 2022 41 3385 3393 35597813
Kerr, A. & Baxter, R. C. Noncoding RNA actions through IGFs and IGF binding proteins in cancer. Oncogene 41, 3385–3393 (2022).35597813
342. Baxter RC Signaling pathways of the insulin-like growth factor binding proteins Endocr. Rev. 2023 44 753 778 36974712
Baxter, R. C. Signaling pathways of the insulin-like growth factor binding proteins. Endocr. Rev. 44, 753–778 (2023).36974712
343. Björndahl M Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo Proc. Natl Acad. Sci. USA 2005 102 15593 15598 16230630
Björndahl, M. et al. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc. Natl Acad. Sci. USA 102, 15593–15598 (2005).16230630
344. Wang SH Tumour cell-derived WNT5B modulates in vitro lymphangiogenesis via induction of partial endothelial-mesenchymal transition of lymphatic endothelial cells Oncogene 2017 36 1503 1515 27593938
Wang, S. H. et al. Tumour cell-derived WNT5B modulates in vitro lymphangiogenesis via induction of partial endothelial-mesenchymal transition of lymphatic endothelial cells. Oncogene 36, 1503–1515 (2017).27593938
345. Lutze G Non-canonical WNT-signaling controls differentiation of lymphatics and extension lymphangiogenesis via RAC and JNK signaling Sci. Rep. 2019 9 4739 30894622
Lutze, G. et al. Non-canonical WNT-signaling controls differentiation of lymphatics and extension lymphangiogenesis via RAC and JNK signaling. Sci. Rep. 9, 4739 (2019).30894622
346. Buttler K Becker J Pukrop T Wilting J Maldevelopment of dermal lymphatics in Wnt5a-knockout-mice Dev. Biol. 2013 381 365 376 23850867
Buttler, K., Becker, J., Pukrop, T. & Wilting, J. Maldevelopment of dermal lymphatics in Wnt5a-knockout-mice. Dev. Biol. 381, 365–376 (2013).23850867
347. Nunan R Ephrin-Bs drive junctional downregulation and actin stress fiber disassembly to enable wound re-epithelialization Cell Rep. 2015 13 1380 1395 26549443
Nunan, R. et al. Ephrin-Bs drive junctional downregulation and actin stress fiber disassembly to enable wound re-epithelialization. Cell Rep. 13, 1380–1395 (2015).26549443
348. Li L EphB4/ephrinB2 contributes to imatinib resistance in chronic myeloid leukemia involved in cytoskeletal proteins Int. J. Med. Sci. 2016 13 365 373 27226777
Li, L. et al. EphB4/ephrinB2 contributes to imatinib resistance in chronic myeloid leukemia involved in cytoskeletal proteins. Int. J. Med. Sci. 13, 365–373 (2016).27226777
349. Wang Y Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis Nature 2010 465 483 486 20445537
Wang, Y. et al. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465, 483–486 (2010).20445537
350. Abéngozar MA Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth Blood 2012 119 4565 4576 22446484
Abéngozar, M. A. et al. Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth. Blood 119, 4565–4576 (2012).22446484
351. Katsuta H EphrinB2-EphB4 signals regulate formation and maintenance of funnel-shaped valves in corneal lymphatic capillaries Investig. Ophthalmol. Vis. Sci. 2013 54 4102 4108 23696610
Katsuta, H. et al. EphrinB2-EphB4 signals regulate formation and maintenance of funnel-shaped valves in corneal lymphatic capillaries. Investig. Ophthalmol. Vis. Sci. 54, 4102–4108 (2013).23696610
352. Hoopes SL Willcockson HH Caron KM Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice PloS One 2012 7 e45261 23028890
Hoopes, S. L., Willcockson, H. H. & Caron, K. M. Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice. PloS One 7, e45261 (2012).23028890
353. Hay DL Walker CS Poyner DR Adrenomedullin and calcitonin gene-related peptide receptors in endocrine-related cancers: opportunities and challenges Endocr. Relat. Cancer 2011 18 C1 C14 21051558
Hay, D. L., Walker, C. S. & Poyner, D. R. Adrenomedullin and calcitonin gene-related peptide receptors in endocrine-related cancers: opportunities and challenges. Endocr. Relat. Cancer 18, C1–C14 (2011).21051558
354. Karpinich NO Adrenomedullin gene dosage correlates with tumor and lymph node lymphangiogenesis FASEB J. 2013 27 590 600 23099649
Karpinich, N. O. et al. Adrenomedullin gene dosage correlates with tumor and lymph node lymphangiogenesis. FASEB J. 27, 590–600 (2013).23099649
355. Yarla NS Targeting arachidonic acid pathway by natural products for cancer prevention and therapy Semin. Cancer Biol. 2016 40-41 48 81 26853158
Yarla, N. S. et al. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin. Cancer Biol. 40-41, 48–81 (2016).26853158
356. Seo MJ Oh DK Prostaglandin synthases: Molecular characterization and involvement in prostaglandin biosynthesis Prog. Lipid Res. 2017 66 50 68 28392405
Seo, M. J. & Oh, D. K. Prostaglandin synthases: Molecular characterization and involvement in prostaglandin biosynthesis. Prog. Lipid Res. 66, 50–68 (2017).28392405
357. Matsuda H Roles of mPGES-1, an inducible prostaglandin E synthase, in enhancement of LPS-induced lymphangiogenesis in a mouse peritonitis model Life Sci. 2015 142 1 7 26459051
Matsuda, H. et al. Roles of mPGES-1, an inducible prostaglandin E synthase, in enhancement of LPS-induced lymphangiogenesis in a mouse peritonitis model. Life Sci. 142, 1–7 (2015).26459051
358. Lala PK Nandi P Majumder M Roles of prostaglandins in tumor-associated lymphangiogenesis with special reference to breast cancer Cancer Metastasis Rev. 2018 37 369 384 29858743
Lala, P. K., Nandi, P. & Majumder, M. Roles of prostaglandins in tumor-associated lymphangiogenesis with special reference to breast cancer. Cancer Metastasis Rev. 37, 369–384 (2018).29858743
359. Nandi P PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells BMC Cancer 2017 17 11 28056899
Nandi, P. et al. PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells. BMC Cancer 17, 11 (2017).28056899
360. Rocha PN Role of thromboxane A2 in the induction of apoptosis of immature thymocytes by lipopolysaccharide Clin. Diagn. Lab. Immunol. 2005 12 896 903 16085905
Rocha, P. N. et al. Role of thromboxane A2 in the induction of apoptosis of immature thymocytes by lipopolysaccharide. Clin. Diagn. Lab. Immunol. 12, 896–903 (2005).16085905
361. Yang CW Unanue ER Neutrophils control the magnitude and spread of the immune response in a thromboxane A2-mediated process J. Exp. Med. 2013 210 375 387 23337807
Yang, C. W. & Unanue, E. R. Neutrophils control the magnitude and spread of the immune response in a thromboxane A2-mediated process. J. Exp. Med. 210, 375–387 (2013).23337807
362. Matsuda H Roles of thromboxane receptor signaling in enhancement of lipopolysaccharide-induced lymphangiogenesis and lymphatic drainage function in diaphragm Arterioscler. Thromb. Vasc. Biol. 2021 41 1390 1407 33567865
Matsuda, H. et al. Roles of thromboxane receptor signaling in enhancement of lipopolysaccharide-induced lymphangiogenesis and lymphatic drainage function in diaphragm. Arterioscler. Thromb. Vasc. Biol. 41, 1390–1407 (2021).33567865
363. Tian W Leukotrienes in tumor-associated inflammation Front. Pharmacol. 2020 11 1289 32973519
Tian, W. et al. Leukotrienes in tumor-associated inflammation. Front. Pharmacol. 11, 1289 (2020).32973519
364. Wang B Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets Signal. Transduct. Target. Ther. 2021 6 94 33637672
Wang, B. et al. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal. Transduct. Target. Ther. 6, 94 (2021).33637672
365. Bhusan Tripathi Y Effect of a dietary supplement on the reduction of lymphedema-progression in mouse tail-cut model Eur. Rev. Med. Pharmacol. Sci. 2021 25 56 66 34890035
Bhusan Tripathi, Y. et al. Effect of a dietary supplement on the reduction of lymphedema-progression in mouse tail-cut model. Eur. Rev. Med. Pharmacol. Sci. 25, 56–66 (2021).34890035
366. Cribb MT The kinetics of lymphatic dysfunction and leukocyte expansion in the draining lymph node during LTB(4) antagonism in a mouse model of lymphedema Int. J. Mol. Sci. 2021 22 4455 33923272
Cribb, M. T. et al. The kinetics of lymphatic dysfunction and leukocyte expansion in the draining lymph node during LTB(4) antagonism in a mouse model of lymphedema. Int. J. Mol. Sci. 22, 4455 (2021).33923272
367. Pyne S Pyne N Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors Pharmacol. Ther. 2000 88 115 131 11150592
Pyne, S. & Pyne, N. Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors. Pharmacol. Ther. 88, 115–131 (2000).11150592
368. Yoon CM Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways Blood 2008 112 1129 1138 18541717
Yoon, C. M. et al. Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways. Blood 112, 1129–1138 (2008).18541717
369. Nagahashi M Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis Cancer Res. 2012 72 726 735 22298596
Nagahashi, M. et al. Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Res. 72, 726–735 (2012).22298596
370. Choi JW LPA receptors: subtypes and biological actions Annu. Rev. Pharmacol. Toxicol. 2010 50 157 186 20055701
Choi, J. W. et al. LPA receptors: subtypes and biological actions. Annu. Rev. Pharmacol. Toxicol. 50, 157–186 (2010).20055701
371. Wu PY Mechanisms of lysophosphatidic acid-mediated lymphangiogenesis in prostate cancer Cancers 2018 10 413 30384405
Wu, P. Y. et al. Mechanisms of lysophosphatidic acid-mediated lymphangiogenesis in prostate cancer. Cancers 10, 413 (2018).30384405
372. Mu H Lysophosphatidic acid induces lymphangiogenesis and IL-8 production in vitro in human lymphatic endothelial cells Am. J. Pathol. 2012 180 2170 2181 22465753
Mu, H. et al. Lysophosphatidic acid induces lymphangiogenesis and IL-8 production in vitro in human lymphatic endothelial cells. Am. J. Pathol. 180, 2170–2181 (2012).22465753
373. Cech TR Steitz JA The noncoding RNA revolution-trashing old rules to forge new ones Cell 2014 157 77 94 24679528
Cech, T. R. & Steitz, J. A. The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157, 77–94 (2014).24679528
374. Li X Long noncoding RNA ASLNC07322 functions in VEGF-C expression regulated by smad4 during colon cancer metastasis Mol. Ther. Nucleic Acids 2019 18 851 862 31739210
Li, X. et al. Long noncoding RNA ASLNC07322 functions in VEGF-C expression regulated by smad4 during colon cancer metastasis. Mol. Ther. Nucleic Acids 18, 851–862 (2019).31739210
375. Wang Y Long noncoding RNA VESTAR regulates lymphangiogenesis and lymph node metastasis of esophageal squamous cell carcinoma by enhancing VEGFC mRNA stability Cancer Res. 2021 81 3187 3199 33771898
Wang, Y. et al. Long noncoding RNA VESTAR regulates lymphangiogenesis and lymph node metastasis of esophageal squamous cell carcinoma by enhancing VEGFC mRNA stability. Cancer Res. 81, 3187–3199 (2021).33771898
376. Zheng H Tumor-derived exosomal BCYRN1 activates WNT5A/VEGF-C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer Clin. Transl. Med. 2021 11 e497 34323412
Zheng, H. et al. Tumor-derived exosomal BCYRN1 activates WNT5A/VEGF-C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer. Clin. Transl. Med. 11, e497 (2021).34323412
377. Misir S Wu N Yang BB Specific expression and functions of circular RNAs Cell Death Differ. 2022 29 481 491 35169296
Misir, S., Wu, N. & Yang, B. B. Specific expression and functions of circular RNAs. Cell Death Differ. 29, 481–491 (2022).35169296
378. Yang L Wilusz JE Chen LL Biogenesis and regulatory roles of circular RNAs Annu. Rev. Cell Dev. Biol. 2022 38 263 289 35609906
Yang, L., Wilusz, J. E. & Chen, L. L. Biogenesis and regulatory roles of circular RNAs. Annu. Rev. Cell Dev. Biol. 38, 263–289 (2022).35609906
379. Yao W Exosomal circ_0026611 contributes to lymphangiogenesis by reducing PROX1 acetylation and ubiquitination in human lymphatic endothelial cells (HLECs) Cell Mol. Biol. Lett. 2023 28 13 36803975
Yao, W. et al. Exosomal circ_0026611 contributes to lymphangiogenesis by reducing PROX1 acetylation and ubiquitination in human lymphatic endothelial cells (HLECs). Cell Mol. Biol. Lett. 28, 13 (2023).36803975
380. Ismail AM Stem cell therapy using bone marrow-derived mononuclear cells in treatment of lower limb lymphedema: a randomized controlled clinical trial Lymphat. Res. Biol. 2018 16 270 277 29912663
Ismail, A. M. et al. Stem cell therapy using bone marrow-derived mononuclear cells in treatment of lower limb lymphedema: a randomized controlled clinical trial. Lymphat. Res. Biol. 16, 270–277 (2018).29912663
381. Kumar NP Banurekha VV Nair D Babu S Circulating angiogenic factors as biomarkers of disease severity and bacterial burden in pulmonary tuberculosis PLoS One 2016 11 e0146318 26727122
Kumar, N. P., Banurekha, V. V., Nair, D. & Babu, S. Circulating angiogenic factors as biomarkers of disease severity and bacterial burden in pulmonary tuberculosis. PLoS One 11, e0146318 (2016).26727122
382. Huber GF Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx Int. J. Cancer 2011 129 1404 1409 21105028
Huber, G. F. et al. Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx. Int. J. Cancer 129, 1404–1409 (2011).21105028
383. Yadav K Immunohistochemistry study of tumor vascular normalization and anti-angiogenic effects of sunitinib versus bevacizumab prior to dose-dense doxorubicin/cyclophosphamide chemotherapy in HER2-negative breast cancer Breast Cancer Res. Treat. 2022 192 131 142 34928481
Yadav, K. et al. Immunohistochemistry study of tumor vascular normalization and anti-angiogenic effects of sunitinib versus bevacizumab prior to dose-dense doxorubicin/cyclophosphamide chemotherapy in HER2-negative breast cancer. Breast Cancer Res. Treat. 192, 131–142 (2022).34928481
384. Wong AL Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer Oncotarget 2016 7 64089 64099 27577069
Wong, A. L. et al. Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer. Oncotarget 7, 64089–64099 (2016).27577069
385. Schoppmann SF HER2/neu expression correlates with vascular endothelial growth factor-C and lymphangiogenesis in lymph node-positive breast cancer Ann. Oncol. 2010 21 955 960 19940005
Schoppmann, S. F. et al. HER2/neu expression correlates with vascular endothelial growth factor-C and lymphangiogenesis in lymph node-positive breast cancer. Ann. Oncol. 21, 955–960 (2010).19940005
386. Qin T Anlotinib suppresses lymphangiogenesis and lymphatic metastasis in lung adenocarcinoma through a process potentially involving VEGFR-3 signaling Cancer Biol. Med. 2020 17 753 767 32944404
Qin, T. et al. Anlotinib suppresses lymphangiogenesis and lymphatic metastasis in lung adenocarcinoma through a process potentially involving VEGFR-3 signaling. Cancer Biol. Med. 17, 753–767 (2020).32944404
387. Ong HS Cytoplasmic neuropilin 2 is associated with metastasis and a poor prognosis in early tongue cancer patients Int. J. Oral. Maxillofac. Surg. 2017 46 1205 1219 28602571
Ong, H. S. et al. Cytoplasmic neuropilin 2 is associated with metastasis and a poor prognosis in early tongue cancer patients. Int. J. Oral. Maxillofac. Surg. 46, 1205–1219 (2017).28602571
388. McCormack FX Efficacy and safety of sirolimus in lymphangioleiomyomatosis N. Engl. J. Med. 2011 364 1595 1606 21410393
McCormack, F. X. et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N. Engl. J. Med. 364, 1595–1606 (2011).21410393
389. Choi I Visualization of lymphatic vessels by Prox1-promoter directed GFP reporter in a bacterial artificial chromosome-based transgenic mouse Blood 2011 117 362 365 20962325
Choi, I. et al. Visualization of lymphatic vessels by Prox1-promoter directed GFP reporter in a bacterial artificial chromosome-based transgenic mouse. Blood 117, 362–365 (2011).20962325
390. González-Hernández S Mukouyama Y-S Lymphatic vasculature in the central nervous system Front. Cell Dev. Biol. 2023 11 1150775 37091974
González-Hernández, S. & Mukouyama, Y.-S. Lymphatic vasculature in the central nervous system. Front. Cell Dev. Biol. 11, 1150775 (2023).37091974
391. Izen RM Postnatal development of lymphatic vasculature in the brain meninges Dev. Dyn. 2018 247 741 753 29493038
Izen, R. M. et al. Postnatal development of lymphatic vasculature in the brain meninges. Dev. Dyn. 247, 741–753 (2018).29493038
392. Bálint L Lymph flow induces the postnatal formation of mature and functional meningeal lymphatic vessels Front. Immunol. 2019 10 3043 31993056
Bálint, L. et al. Lymph flow induces the postnatal formation of mature and functional meningeal lymphatic vessels. Front. Immunol. 10, 3043 (2019).31993056
393. Ahn JH Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid Nature 2019 572 62 66 31341278
Ahn, J. H. et al. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62–66 (2019).31341278
394. Kapiainen E Cooperation of angiopoietin-2 and angiopoietin-4 in Schlemm’s canal maintenance Investig. Ophthalmol. Vis. Sci. 2022 63 1
Kapiainen, E. et al. Cooperation of angiopoietin-2 and angiopoietin-4 in Schlemm’s canal maintenance. Investig. Ophthalmol. Vis. Sci. 63, 1 (2022).
395. Wu Y Organogenesis and distribution of the ocular lymphatic vessels in the anterior eye JCI Insight 2020 5 e135121 32641580
Wu, Y. et al. Organogenesis and distribution of the ocular lymphatic vessels in the anterior eye. JCI Insight 5, e135121 (2020).32641580
396. Kizhatil K Schlemm’s canal is a unique vessel with a combination of blood vascular and lymphatic phenotypes that forms by a novel developmental process PLoS Biol. 2014 12 e1001912 25051267
Kizhatil, K. et al. Schlemm’s canal is a unique vessel with a combination of blood vascular and lymphatic phenotypes that forms by a novel developmental process. PLoS Biol. 12, e1001912 (2014).25051267
397. Park D-Y Lymphatic regulator PROX1 determines Schlemm’s canal integrity and identity J. Clin. Invest. 2014 124 3960 3974 25061877
Park, D.-Y. et al. Lymphatic regulator PROX1 determines Schlemm’s canal integrity and identity. J. Clin. Invest. 124, 3960–3974 (2014).25061877
398. Du J Thomson BR Onay T Quaggin SE Endothelial tyrosine kinase Tie1 is required for normal schlemm’s canal development-brief report Arterioscler. Thromb. Vasc. Biol. 2022 42 348 351 35021855
Du, J., Thomson, B. R., Onay, T. & Quaggin, S. E. Endothelial tyrosine kinase Tie1 is required for normal schlemm’s canal development-brief report. Arterioscler. Thromb. Vasc. Biol. 42, 348–351 (2022).35021855
399. Thomson BR Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies Nat. Commun. 2021 12 6072 34663817
Thomson, B. R. et al. Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies. Nat. Commun. 12, 6072 (2021).34663817
400. Gancz D Perlmoter G Yaniv K Formation and growth of cardiac lymphatics during embryonic development, heart regeneration, and disease Cold Spring Harb. Perspect. Biol. 2020 12 a037176 31818858
Gancz, D., Perlmoter, G. & Yaniv, K. Formation and growth of cardiac lymphatics during embryonic development, heart regeneration, and disease. Cold Spring Harb. Perspect. Biol. 12, a037176 (2020).31818858
401. Harrison MR Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration Elife 2019 8 e42762 31702553
Harrison, M. R. et al. Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration. Elife 8, e42762 (2019).31702553
402. Harris NR VE-Cadherin is required for cardiac lymphatic maintenance and signaling Circ. Res. 2022 130 5 23 34789016
Harris, N. R. et al. VE-Cadherin is required for cardiac lymphatic maintenance and signaling. Circ. Res. 130, 5–23 (2022).34789016
403. Xu W Small GTPase Rap1A/B is required for lymphatic development and adrenomedullin-induced stabilization of lymphatic endothelial junctions Arterioscler. Thromb. Vasc. Biol. 2018 38 2410 2422 30354217
Xu, W. et al. Small GTPase Rap1A/B is required for lymphatic development and adrenomedullin-induced stabilization of lymphatic endothelial junctions. Arterioscler. Thromb. Vasc. Biol. 38, 2410–2422 (2018).30354217
404. Martucciello S A dual role for Tbx1 in cardiac lymphangiogenesis through genetic interaction with Vegfr3 FASEB J. 2020 34 15062 15079 32951265
Martucciello, S. et al. A dual role for Tbx1 in cardiac lymphangiogenesis through genetic interaction with Vegfr3. FASEB J. 34, 15062–15079 (2020).32951265
405. Trivedi A Reed HO The lymphatic vasculature in lung function and respiratory disease Front. Med. 2023 10 1118583
Trivedi, A. & Reed, H. O. The lymphatic vasculature in lung function and respiratory disease. Front. Med. 10, 1118583 (2023).
406. Yao L-C Pulmonary lymphangiectasia resulting from vascular endothelial growth factor-C overexpression during a critical period Circ. Res. 2014 114 806 822 24429550
Yao, L.-C. et al. Pulmonary lymphangiectasia resulting from vascular endothelial growth factor-C overexpression during a critical period. Circ. Res. 114, 806–822 (2014).24429550
407. Fu S c-JUN-mediated transcriptional responses in lymphatic endothelial cells are required for lung fluid clearance at birth Proc. Natl Acad. Sci. USA 2023 120 e2215449120 36595691
Fu, S. et al. c-JUN-mediated transcriptional responses in lymphatic endothelial cells are required for lung fluid clearance at birth. Proc. Natl Acad. Sci. USA 120, e2215449120 (2023).36595691
408. Bobe S Volumetric imaging reveals VEGF-C-dependent formation of hepatic lymph vessels in mice Front. Cell Dev. Biol. 2022 10 949896 36051444
Bobe, S. et al. Volumetric imaging reveals VEGF-C-dependent formation of hepatic lymph vessels in mice. Front. Cell Dev. Biol. 10, 949896 (2022).36051444
409. Tanaka M Iwakiri Y The hepatic lymphatic vascular system: structure, function, markers, and lymphangiogenesis Cell Mol. Gastroenterol. Hepatol. 2016 2 733 749 28105461
Tanaka, M. & Iwakiri, Y. The hepatic lymphatic vascular system: structure, function, markers, and lymphangiogenesis. Cell Mol. Gastroenterol. Hepatol. 2, 733–749 (2016).28105461
410. Huang S Three-dimensional mapping of hepatic lymphatic vessels and transcriptome profiling of lymphatic endothelial cells in healthy and diseased livers Theranostics 2023 13 639 658 36632228
Huang, S. et al. Three-dimensional mapping of hepatic lymphatic vessels and transcriptome profiling of lymphatic endothelial cells in healthy and diseased livers. Theranostics 13, 639–658 (2023).36632228
411. Crosswhite PL CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity J. Clin. Investig. 2016 126 2254 2266 27140400
Crosswhite, P. L. et al. CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity. J. Clin. Investig. 126, 2254–2266 (2016).27140400
412. Mahadevan A The left-right Pitx2 pathway drives organ-specific arterial and lymphatic development in the intestine Dev. Cell 2014 31 690 706 25482882
Mahadevan, A. et al. The left-right Pitx2 pathway drives organ-specific arterial and lymphatic development in the intestine. Dev. Cell 31, 690–706 (2014).25482882
413. Shimoda H Abnormal recruitment of periendothelial cells to lymphatic capillaries in digestive organs of angiopoietin-2-deficient mice Cell Tissue Res. 2007 328 329 337 17235601
Shimoda, H. et al. Abnormal recruitment of periendothelial cells to lymphatic capillaries in digestive organs of angiopoietin-2-deficient mice. Cell Tissue Res. 328, 329–337 (2007).17235601
414. Davis RB Lymphatic deletion of calcitonin receptor-like receptor exacerbates intestinal inflammation JCI Insight 2017 2 e92465 28352669
Davis, R. B. et al. Lymphatic deletion of calcitonin receptor-like receptor exacerbates intestinal inflammation. JCI Insight 2, e92465 (2017).28352669
415. Mouta-Bellum C Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85alpha, p55alpha, and p50alpha Dev. Dyn. 2009 238 2670 2679 19705443
Mouta-Bellum, C. et al. Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85alpha, p55alpha, and p50alpha. Dev. Dyn. 238, 2670–2679 (2009).19705443
416. Chen D RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development J. Clin. Invest. 2019 129 3545 3561 31185000
Chen, D. et al. RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development. J. Clin. Invest. 129, 3545–3561 (2019).31185000
417. Qin L CCM3 loss-induced lymphatic defect is mediated by the augmented VEGFR3-ERK1/2 signaling Arterioscler. Thromb. Vasc. Biol. 2021 41 2943 2960 34670407
Qin, L. et al. CCM3 loss-induced lymphatic defect is mediated by the augmented VEGFR3-ERK1/2 signaling. Arterioscler. Thromb. Vasc. Biol. 41, 2943–2960 (2021).34670407
418. Saharinen P Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development Genes Dev. 2010 24 875 880 20439428
Saharinen, P. et al. Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development. Genes Dev. 24, 875–880 (2010).20439428
419. Kenig-Kozlovsky Y Ascending vasa recta are angiopoietin/Tie2-dependent lymphatic-like vessels J. Am. Soc. Nephrol. 2018 29 1097 1107 29237738
Kenig-Kozlovsky, Y. et al. Ascending vasa recta are angiopoietin/Tie2-dependent lymphatic-like vessels. J. Am. Soc. Nephrol. 29, 1097–1107 (2018).29237738
420. Jafree DJ Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease Elife 2019 8 e48183 31808745
Jafree, D. J. et al. Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease. Elife 8, e48183 (2019).31808745
421. Muley A Unique functions for Notch4 in murine embryonic lymphangiogenesis Angiogenesis 2022 25 205 224 34665379
Muley, A. et al. Unique functions for Notch4 in murine embryonic lymphangiogenesis. Angiogenesis 25, 205–224 (2022).34665379
422. Niessen K The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development Blood 2011 118 1989 1997 21700774
Niessen, K. et al. The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development. Blood 118, 1989–1997 (2011).21700774
423. Brown HM Russell DL Blood and lymphatic vasculature in the ovary: development, function and disease Hum. Reprod. Update 2014 20 29 39 24097804
Brown, H. M. & Russell, D. L. Blood and lymphatic vasculature in the ovary: development, function and disease. Hum. Reprod. Update 20, 29–39 (2014).24097804
424. Brown HM Robker RL Russell DL Development and hormonal regulation of the ovarian lymphatic vasculature Endocrinology 2010 151 5446 5455 20843998
Brown, H. M., Robker, R. L. & Russell, D. L. Development and hormonal regulation of the ovarian lymphatic vasculature. Endocrinology 151, 5446–5455 (2010).20843998
425. Brown HM Requirement for ADAMTS-1 in extracellular matrix remodeling during ovarian folliculogenesis and lymphangiogenesis Dev. Biol. 2006 300 699 709 17097630
Brown, H. M. et al. Requirement for ADAMTS-1 in extracellular matrix remodeling during ovarian folliculogenesis and lymphangiogenesis. Dev. Biol. 300, 699–709 (2006).
426. van Impel A Divergence of zebrafish and mouse lymphatic cell fate specification pathways Development 2014 141 1228 1238 24523456
van Impel, A. et al. Divergence of zebrafish and mouse lymphatic cell fate specification pathways. Development 141, 1228–1238 (2014).24523456
427. Grimm L Single-cell analysis of lymphatic endothelial cell fate specification and differentiation during zebrafish development EMBO J. 2023 42 e112590 36912146
Grimm, L. et al. Single-cell analysis of lymphatic endothelial cell fate specification and differentiation during zebrafish development. EMBO J. 42, e112590 (2023).36912146
428. Del Giacco L Pistocchi A Ghilardi A prox1b Activity is essential in zebrafish lymphangiogenesis PLoS One 2010 5 e13170 20976189
Del Giacco, L., Pistocchi, A. & Ghilardi, A. prox1b Activity is essential in zebrafish lymphangiogenesis. PLoS One 5, e13170 (2010).20976189
429. Astin JW Vegfd can compensate for loss of Vegfc in zebrafish facial lymphatic sprouting Development 2014 141 2680 2690 24903752
Astin, J. W. et al. Vegfd can compensate for loss of Vegfc in zebrafish facial lymphatic sprouting. Development 141, 2680–2690 (2014).24903752
430. Bower NI Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development Development 2017 144 507 518 28087639
Bower, N. I. et al. Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development. Development 144, 507–518 (2017).28087639
431. Vogrin AJ Evolutionary differences in the Vegf/Vegfr code reveal organotypic roles for the endothelial cell receptor Kdr in developmental lymphangiogenesis Cell Rep. 2019 28 2023 2036.e4 31433980
Vogrin, A. J. et al. Evolutionary differences in the Vegf/Vegfr code reveal organotypic roles for the endothelial cell receptor Kdr in developmental lymphangiogenesis. Cell Rep. 28, 2023–2036.e4 (2019).31433980
432. Wang G Specific fibroblast subpopulations and neuronal structures provide local sources of Vegfc-processing components during zebrafish lymphangiogenesis Nat. Commun. 2020 11 2724 32483144
Wang, G. et al. Specific fibroblast subpopulations and neuronal structures provide local sources of Vegfc-processing components during zebrafish lymphangiogenesis. Nat. Commun. 11, 2724 (2020).32483144
433. Dupont L ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in adults for pro-VEGFC activation and lymphatic homeostasis JCI Insight 2022 7 e151509 35316211
Dupont, L. et al. ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in adults for pro-VEGFC activation and lymphatic homeostasis. JCI Insight 7, e151509 (2022).35316211
434. Le Guen L Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis Development 2014 141 1239 1249 24523457
Le Guen, L. et al. Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis. Development 141, 1239–1249 (2014).24523457
435. Cermenati S Sox18 genetically interacts with VegfC to regulate lymphangiogenesis in zebrafish Arterioscler. Thromb. Vasc. Biol. 2013 33 1238 1247 23520166
Cermenati, S. et al. Sox18 genetically interacts with VegfC to regulate lymphangiogenesis in zebrafish. Arterioscler. Thromb. Vasc. Biol. 33, 1238–1247 (2013).23520166
436. Das RN Generation of specialized blood vessels via lymphatic transdifferentiation Nature 2022 606 570 575 35614218
Das, R. N. et al. Generation of specialized blood vessels via lymphatic transdifferentiation. Nature 606, 570–575 (2022).35614218
437. Gauvrit S HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development Nat. Commun. 2018 9 2704 30006544
Gauvrit, S. et al. HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development. Nat. Commun. 9, 2704 (2018).30006544
438. Arnold H mafba and mafbb differentially regulate lymphatic endothelial cell migration in topographically distinct manners Cell Rep. 2022 39 110982 35732122
Arnold, H. et al. mafba and mafbb differentially regulate lymphatic endothelial cell migration in topographically distinct manners. Cell Rep. 39, 110982 (2022).35732122
439. Shin M Valves are a conserved feature of the zebrafish lymphatic system Dev. Cell 2019 51 374 386.e5 31564611
Shin, M. et al. Valves are a conserved feature of the zebrafish lymphatic system. Dev. Cell 51, 374–386.e5 (2019).31564611
440. Meng Y Temporospatial inhibition of Erk signaling is required for lymphatic valve formation Signal. Transduct. Target. Ther. 2023 8 342 37691058
Meng, Y. et al. Temporospatial inhibition of Erk signaling is required for lymphatic valve formation. Signal. Transduct. Target. Ther. 8, 342 (2023).37691058
441. Peng D Proper migration of lymphatic endothelial cells requires survival and guidance cues from arterial mural cells Elife 2022 11 e74094 35316177
Peng, D. et al. Proper migration of lymphatic endothelial cells requires survival and guidance cues from arterial mural cells. Elife 11, e74094 (2022).35316177
442. Dunworth WP Bone morphogenetic protein 2 signaling negatively modulates lymphatic development in vertebrate embryos Circ. Res. 2014 114 56 66 24122719
Dunworth, W. P. et al. Bone morphogenetic protein 2 signaling negatively modulates lymphatic development in vertebrate embryos. Circ. Res. 114, 56–66 (2014).24122719
443. Pedrioli DML miR-31 functions as a negative regulator of lymphatic vascular lineage-specific differentiation in vitro and vascular development in vivo Mol. Cell Biol. 2010 30 3620 3634 20479124
Pedrioli, D. M. L. et al. miR-31 functions as a negative regulator of lymphatic vascular lineage-specific differentiation in vitro and vascular development in vivo. Mol. Cell Biol. 30, 3620–3634 (2010).20479124
444. Geudens I Role of delta-like-4/Notch in the formation and wiring of the lymphatic network in zebrafish Arterioscler. Thromb. Vasc. Biol. 2010 30 1695 1702 20466977
Geudens, I. et al. Role of delta-like-4/Notch in the formation and wiring of the lymphatic network in zebrafish. Arterioscler. Thromb. Vasc. Biol. 30, 1695–1702 (2010).20466977
445. Britto DD Plexin D1 negatively regulates zebrafish lymphatic development Development 2022 149 dev200560 36205097
Britto, D. D. et al. Plexin D1 negatively regulates zebrafish lymphatic development. Development 149, dev200560 (2022).36205097
446. Kim J-D Essential role of Apelin signaling during lymphatic development in zebrafish Arterioscler. Thromb. Vasc. Biol. 2014 34 338 345 24311379
Kim, J.-D. et al. Essential role of Apelin signaling during lymphatic development in zebrafish. Arterioscler. Thromb. Vasc. Biol. 34, 338–345 (2014).24311379
447. Huang H The RAS guanyl nucleotide-releasing protein RasGRP1 is involved in lymphatic development in zebrafish J. Biol. Chem. 2013 288 2355 2364 23184941
Huang, H. et al. The RAS guanyl nucleotide-releasing protein RasGRP1 is involved in lymphatic development in zebrafish. J. Biol. Chem. 288, 2355–2364 (2013).23184941
448. Lei D Noncanonical protease-activated receptor 1 regulates lymphatic differentiation in zebrafish iScience 2021 24 103386 34816109
Lei, D. et al. Noncanonical protease-activated receptor 1 regulates lymphatic differentiation in zebrafish. iScience 24, 103386 (2021).34816109
449. Yan H CD146 is required for VEGF-C-induced lymphatic sprouting during lymphangiogenesis Sci. Rep. 2017 7 7442 28785085
Yan, H. et al. CD146 is required for VEGF-C-induced lymphatic sprouting during lymphangiogenesis. Sci. Rep. 7, 7442 (2017).28785085
450. Hußmann M Svep1 is a binding ligand of Tie1 and affects specific aspects of facial lymphatic development in a Vegfc-independent manner Elife 2023 12 e82969 37097004
Hußmann, M. et al. Svep1 is a binding ligand of Tie1 and affects specific aspects of facial lymphatic development in a Vegfc-independent manner. Elife 12, e82969 (2023).37097004
451. Mauri C van Impel A Mackay EW Schulte-Merker S The adaptor protein Grb2b is an essential modulator for lympho-venous sprout formation in the zebrafish trunk Angiogenesis 2021 24 345 362 33677657
Mauri, C., van Impel, A., Mackay, E. W. & Schulte-Merker, S. The adaptor protein Grb2b is an essential modulator for lympho-venous sprout formation in the zebrafish trunk. Angiogenesis 24, 345–362 (2021).33677657
452. Coxam B Pkd1 regulates lymphatic vascular morphogenesis during development Cell Rep. 2014 7 623 633 24767999
Coxam, B. et al. Pkd1 regulates lymphatic vascular morphogenesis during development. Cell Rep. 7, 623–633 (2014).24767999
453. Chau TCY Pkd1 and Wnt5a genetically interact to control lymphatic vascular morphogenesis in mice Dev. Dyn. 2022 251 336 349 34174014
Chau, T. C. Y. et al. Pkd1 and Wnt5a genetically interact to control lymphatic vascular morphogenesis in mice. Dev. Dyn. 251, 336–349 (2022).34174014
454. Hermans K Role of synectin in lymphatic development in zebrafish and frogs Blood 2010 116 3356 3366 20631376
Hermans, K. et al. Role of synectin in lymphatic development in zebrafish and frogs. Blood 116, 3356–3366 (2010).20631376
455. Grimm L Yap1 promotes sprouting and proliferation of lymphatic progenitors downstream of Vegfc in the zebrafish trunk Elife 2019 8 e42881 31038457
Grimm, L. et al. Yap1 promotes sprouting and proliferation of lymphatic progenitors downstream of Vegfc in the zebrafish trunk. Elife 8, e42881 (2019).31038457
456. Koltowska K The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53 function Nat. Cell Biol. 2021 23 1136 1147 34750583
Koltowska, K. et al. The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53 function. Nat. Cell Biol. 23, 1136–1147 (2021).34750583
457. Lim AH Motoneurons are essential for vascular pathfinding Development 2011 138 3847 3857 21828101
Lim, A. H. et al. Motoneurons are essential for vascular pathfinding. Development 138, 3847–3857 (2011).21828101
458. Baek S The alternative splicing regulator Nova2 constrains vascular ERK signaling to limit specification of the lymphatic lineage Dev. Cell 2019 49 279 292.e5 31014480
Baek, S. et al. The alternative splicing regulator Nova2 constrains vascular ERK signaling to limit specification of the lymphatic lineage. Dev. Cell 49, 279–292.e5 (2019).31014480
459. de Oliveira MB Vasohibin 1 selectively regulates secondary sprouting and lymphangiogenesis in the zebrafish trunk Development 2021 148 dev194993 33547133
de Oliveira, M. B. et al. Vasohibin 1 selectively regulates secondary sprouting and lymphangiogenesis in the zebrafish trunk. Development 148, dev194993 (2021).33547133
460. Chen J MicroRNA-126a directs lymphangiogenesis through interacting with chemokine and Flt4 signaling in zebrafish Arterioscler. Thromb. Vasc. Biol. 2016 36 2381 2393 27789478
Chen, J. et al. MicroRNA-126a directs lymphangiogenesis through interacting with chemokine and Flt4 signaling in zebrafish. Arterioscler. Thromb. Vasc. Biol. 36, 2381–2393 (2016).27789478
461. Kontarakis Z Mir-126 is a conserved modulator of lymphatic development Dev. Biol. 2018 437 120 130 29550364
Kontarakis, Z. et al. Mir-126 is a conserved modulator of lymphatic development. Dev. Biol. 437, 120–130 (2018).29550364
462. Jung HM MicroRNA-mediated control of developmental lymphangiogenesis Elife 2019 8 e46007 31478836
Jung, H. M. et al. MicroRNA-mediated control of developmental lymphangiogenesis. Elife 8, e46007 (2019).31478836
463. Kiesow K Junb controls lymphatic vascular development in zebrafish via miR-182 Sci. Rep. 2015 5 15007 26458334
Kiesow, K. et al. Junb controls lymphatic vascular development in zebrafish via miR-182. Sci. Rep. 5, 15007 (2015).26458334
464. Baluk P Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation J. Clin. Investig. 2005 115 247 257 15668734
Baluk, P. et al. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J. Clin. Investig. 115, 247–257 (2005).15668734
465. Mori M Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD Respir. Res. 2013 14 65 23758732
Mori, M. et al. Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD. Respir. Res. 14, 65 (2013).23758732
466. Shin K TH2 cells and their cytokines regulate formation and function of lymphatic vessels Nat. Commun. 2015 6 6196 25648335
Shin, K. et al. TH2 cells and their cytokines regulate formation and function of lymphatic vessels. Nat. Commun. 6, 6196 (2015).25648335
467. Harding J Lymphangiogenesis is induced by mycobacterial granulomas via vascular endothelial growth factor receptor-3 and supports systemic T-cell responses against mycobacterial antigen Am. J. Pathol. 2015 185 432 445 25597700
Harding, J. et al. Lymphangiogenesis is induced by mycobacterial granulomas via vascular endothelial growth factor receptor-3 and supports systemic T-cell responses against mycobacterial antigen. Am. J. Pathol. 185, 432–445 (2015).25597700
468. Lerner TR Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis J. Clin. Investig. 2016 126 1093 1108 26901813
Lerner, T. R. et al. Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis. J. Clin. Investig. 126, 1093–1108 (2016).26901813
469. El-Chemaly S Abnormal lymphangiogenesis in idiopathic pulmonary fibrosis with insights into cellular and molecular mechanisms Proc. Natl Acad. Sci. USA 2009 106 3958 3963 19237567
El-Chemaly, S. et al. Abnormal lymphangiogenesis in idiopathic pulmonary fibrosis with insights into cellular and molecular mechanisms. Proc. Natl Acad. Sci. USA 106, 3958–3963 (2009).19237567
470. Meinecke A-K Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis Blood 2012 119 5931 5942 22547584
Meinecke, A.-K. et al. Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis. Blood 119, 5931–5942 (2012).22547584
471. Heron C Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure Cardiovasc. Res. 2023 119 492 505 35689481
Heron, C. et al. Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure. Cardiovasc. Res. 119, 492–505 (2023).35689481
472. Lin Q-Y VEGF-C/VEGFR-3 axis protects against pressure-overload induced cardiac dysfunction through regulation of lymphangiogenesis Clin. Transl. Med. 2021 11 e374 33783987
Lin, Q.-Y. et al. VEGF-C/VEGFR-3 axis protects against pressure-overload induced cardiac dysfunction through regulation of lymphangiogenesis. Clin. Transl. Med. 11, e374 (2021).33783987
473. Singla B Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis Cardiovasc. Res. 2021 117 1489 1509 32750106
Singla, B. et al. Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis. Cardiovasc. Res. 117, 1489–1509 (2021).32750106
474. Ishikawa Y Lymphangiogenesis in myocardial remodelling after infarction Histopathology 2007 51 345 353 17727476
Ishikawa, Y. et al. Lymphangiogenesis in myocardial remodelling after infarction. Histopathology 51, 345–353 (2007).17727476
475. Liu X Lymphoangiocrine signals promote cardiac growth and repair Nature 2020 588 705 711 33299187
Liu, X. et al. Lymphoangiocrine signals promote cardiac growth and repair. Nature 588, 705–711 (2020).33299187
476. Wang W Lymphatic endothelial transcription factor Tbx1 promotes an immunosuppressive microenvironment to facilitate post-myocardial infarction repair Immunity 2023 56 2342 2357 37625409
Wang, W. et al. Lymphatic endothelial transcription factor Tbx1 promotes an immunosuppressive microenvironment to facilitate post-myocardial infarction repair. Immunity 56, 2342–2357 (2023).37625409
477. Tamburini BAJ Chronic liver disease in humans causes expansion and differentiation of liver lymphatic endothelial cells Front. Immunol. 2019 10 1036 31156626
Tamburini, B. A. J. et al. Chronic liver disease in humans causes expansion and differentiation of liver lymphatic endothelial cells. Front. Immunol. 10, 1036 (2019).31156626
478. Burchill MA Oxidized low-density lipoprotein drives dysfunction of the liver lymphatic system Cell Mol. Gastroenterol. Hepatol. 2021 11 573 595 32961356
Burchill, M. A. et al. Oxidized low-density lipoprotein drives dysfunction of the liver lymphatic system. Cell Mol. Gastroenterol. Hepatol. 11, 573–595 (2021).32961356
479. Tanaka, M. et al. The sympathetic nervous system promotes hepatic lymphangiogenesis, which is protective against liver fibrosis. Am. J. Pathol. 193, 2182–2202 (2023).
480. Li W-N Extracellular vesicle-associated VEGF-C promotes lymphangiogenesis and immune cells infiltration in endometriosis Proc. Natl Acad. Sci. USA 2020 117 25859 25868 33004630
Li, W.-N. et al. Extracellular vesicle-associated VEGF-C promotes lymphangiogenesis and immune cells infiltration in endometriosis. Proc. Natl Acad. Sci. USA 117, 25859–25868 (2020).33004630
481. Li J Promotion of BST2 expression by the transcription factor IRF6 affects the progression of endometriosis Front. Immunol. 2023 14 1115504 37143676
Li, J. et al. Promotion of BST2 expression by the transcription factor IRF6 affects the progression of endometriosis. Front. Immunol. 14, 1115504 (2023).37143676
482. Guo R Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis Arthritis Rheum. 2009 60 2666 2676 19714652
Guo, R. et al. Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheum. 60, 2666–2676 (2009).19714652
483. Lin X Targeting synovial lymphatic function as a novel therapeutic intervention for age-related osteoarthritis in mice Arthritis Rheumatol. 2023 75 923 936 36625730
Lin, X. et al. Targeting synovial lymphatic function as a novel therapeutic intervention for age-related osteoarthritis in mice. Arthritis Rheumatol. 75, 923–936 (2023).36625730
