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bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.18.607045
preprint
1
Article
Endothelial β1 Integrins are Necessary for Microvascular Function and Glucose Uptake
Winn Nathan C. http://orcid.org/0000-0002-5276-0592

Roby Deborah A. http://orcid.org/0000-0001-6392-177X

McClatchey P. Mason http://orcid.org/0000-0002-6187-3273

Williams Ian M.
Bracy Deanna P.
Bedenbaugh Michelle N.
Lantier Louise http://orcid.org/0000-0002-6620-4976

Plosa Erin J. http://orcid.org/0000-0001-7165-1722

Pozzi Ambra http://orcid.org/0000-0001-8502-1481

Zent Roy http://orcid.org/0000-0003-2983-8133

Wasserman David H. http://orcid.org/0000-0002-3095-2665

19 8 2024
2024.08.18.607045https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.18.607045
nihpp-2024.08.18.607045.pdf
Abstract

Microvascular insulin delivery to myocytes is rate limiting for the onset of insulin-stimulated muscle glucose uptake. The structural integrity of capillaries of the microvasculature is regulated, in part, by a family of transmembrane adhesion receptors known as integrins, which are composed of an α and β subunit. The integrin β1 (itgβ1) subunit is highly expressed in endothelial cells (EC). EC itgβ1 is necessary for the formation of capillary networks during embryonic during development and its knockdown in adult mice blunts the reactive hyperemia that manifests during ischemia reperfusion. In this study we investigated the contribution of skeletal muscle EC itgβ1 in microcirculatory function and glucose uptake. We hypothesized that loss of EC itgβ1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating ‘delivery’-mediated insulin resistance. An itgβ1 knockdown mouse model was developed to avoid lethality of embryonic gene knockout and the deteriorating health resulting from early post-natal inducible gene deletion. We found that mice with (itgβ1 fl/fl SCLcre) and without (itgβ1 fl/fl ) inducible stem cell leukemia cre recombinase (SLCcre) expression at 10 days post cre induction have comparable exercise tolerance and pulmonary and cardiac functions. We quantified microcirculatory hemodynamics using intravital microscopy and the ability of mice to respond to the high metabolic demands of insulin-stimulated muscle using a hyperinsulinemic-euglycemia clamp. We show that itgβ1 fl/fl SCLcre mice compared to itgβ1 fl/fl littermates have, i) deficits in capillary flow rate, flow heterogeneity, and capillary density; ii) impaired insulin-stimulated glucose uptake despite sufficient transcapillary insulin efflux; and iii) reduced insulin-stimulated glucose uptake due to perfusion-limited glucose delivery. Thus, EC itgβ1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation.
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