Endothelial Insulin Receptors and VEGF Signaling

Andrew M N Walker, Nele Warmke, Ben Mercer, Nicole T Watt, Romana Mughal, Jessica Smith, Stacey Galloway, Natalie J Haywood, Taha Soomro, Kathryn J Griffin, Stephen B Wheatcroft, Nadira Y Yuldasheva, David J Beech, Peter Carmeliet, Mark T Kearney, Richard M Cubbon
Endocrinology, Volume 162, Issue 8, August 2021, bqab104
https://doi.org/10.1210/endocr/bqab104

Abstract

Endothelial insulin receptors (Insr) promote sprouting angiogenesis, although the underpinning cellular and molecular mechanisms are unknown. Comparing mice with whole-body insulin receptor haploinsufficiency (Insr^+∕−) against littermate controls, we found impaired limb perfusion and muscle capillary density after inducing hind-limb ischemia; this was in spite of increased expression of the proangiogenic growth factor Vegfa. Insr^+∕− neonatal retinas exhibited reduced tip cell number and branching complexity during developmental angiogenesis, which was also found in separate studies of mice with endothelium-restricted Insr haploinsufficiency. Functional responses to vascular endothelial growth factor A (VEGF-A), including in vitro angiogenesis, were also impaired in aortic rings and pulmonary endothelial cells from Insr^+∕− mice. Human umbilical vein endothelial cells with shRNA-mediated knockdown of Insr also demonstrated impaired functional angiogenic responses to VEGF-A. VEGF-A signaling to Akt and endothelial nitric oxide synthase was intact, but downstream signaling to extracellular signal-reduced kinase 1/2 (ERK1/2) was impaired, as was VEGF receptor-2 (VEGFR-2) internalization, which is required specifically for signaling to ERK1/2. Hence, endothelial insulin receptors facilitate the functional response to VEGF-A during angiogenic sprouting and are required for appropriate signal transduction from VEGFR-2 to ERK1/2.

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