Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis

• Published in: Endocrinology (Philadelphia) Vol. 162; no. 8; p. 1
• Main Authors: Walker, Andrew M N, Warmke, Nele, Mercer, Ben, Watt, Nicole T, Mughal, Romana, Smith, Jessica, Galloway, Stacey, Haywood, Natalie J, Soomro, Taha, Griffin, Kathryn J, Wheatcroft, Stephen B, Yuldasheva, Nadira Y, Beech, David J, Carmeliet, Peter, Kearney, Mark T, Cubbon, Richard M
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.08.2021
• Subjects: AKT protein; Angiogenesis; Animals; Aorta; Aprotinin; Cell number; Cellular signal transduction; Diabetes therapy; Endocrinology; Endothelial cells; Endothelium; Endothelium, Vascular - metabolism; Ethylenediaminetetraacetic acid; Extracellular signal-regulated kinase; Growth factors; Haploinsufficiency; Human Umbilical Vein Endothelial Cells; Humans; Insulin; Insulin receptors; Internalization; Ischemia; Kinases; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular modelling; Neonates; Neovascularization, Pathologic; Neovascularization, Physiologic; Nitric oxide; Nitric-oxide synthase; Receptor, Insulin - metabolism; Receptors; Signal transduction; Umbilical vein; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular endothelial growth factor receptors; United Kingdom; insulin; vascular; angiogenesis; endothelial; VEGF; ERK
• ISSN: 0013-7227; 1945-7170
• DOI: 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.