Endothelial β1 Integrins are Necessary for Microvascular Function and Glucose Uptake

Winn, N. C.; Roby, D. A.; McClatchey, P. M.; Williams, I. M.; Bracy, D. P.; Bedenbaugh, M. N.; Lantier, L.; Plosa, E. J.; Pozzi, A.; Zent, R.; Wasserman, D. H.

doi:10.1101/2024.08.18.607045

bioRxiv · 10.1101/2024.08.18.607045

Endothelial β1 Integrins are Necessary for Microvascular Function and Glucose Uptake

Winn, N. C.·Roby, D. A.·McClatchey, P. M.·Williams, I. M.·Bracy, D. P.·Bedenbaugh, M. N.·Lantier, L.·Plosa, E. J.·Pozzi, A.·Zent, R.·Wasserman, D. H.

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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 and {beta} subunit. The integrin {beta}1 (itg{beta}1) subunit is highly expressed in endothelial cells (EC). EC itg{beta}1 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 itg{beta}1 in microcirculatory function and glucose uptake. We hypothesized that loss of EC itg{beta}1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating delivery-mediated insulin resistance. An itg{beta}1 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 (itg{beta}1fl/flSCLcre) and without (itg{beta}1fl/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 itg{beta}1fl/flSCLcre mice compared to itg{beta}1fl/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 itg{beta}1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation.

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Winn, N. C., Roby, D. A., McClatchey, P. M., Williams, I. M., Bracy, D. P., Bedenbaugh, M. N., Lantier, L., Plosa, E. J., Pozzi, A., Zent, R., Wasserman, D. H.. 2024-08-19. Endothelial β1 Integrins are Necessary for Microvascular Function and Glucose Uptake. https://doi.org/10.1101/2024.08.18.607045

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