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

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.

• Authors: 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
• Journal: Endocrinology (Endocrinology) Vol. 162 Issue 8 (08 01 2021) ISSN: 1945-7170 [Electronic] United States
• PMID: 34037749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Chemical References

• Vascular Endothelial Growth Factor A
• Kdr protein, mouse
• Receptor, Insulin
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Animals
• Endothelium, Vascular (metabolism)
• Human Umbilical Vein Endothelial Cells
• Humans
• MAP Kinase Signaling System
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Pathologic
• Neovascularization, Physiologic
• Receptor, Insulin (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Mice