The role of pericyte insulin signalling

• Main Author: Warmke, Nele
• Format: Dissertation
• Language: English
• Published: University of Leeds 2020

Pericytes are vascular mural cells, essential for vascular remodelling and homeostasis, and key to the pathophysiology of diabetic microangiopathies. Pericytes themselves express the insulin receptor; however, the role of pericyte insulin signalling remains entirely unexplored. Therefore, we investigated how deletion of the insulin receptor in pericytes influenced developmental angiogenesis and whether it has implications on whole-body glucose and lipid metabolism. PDGFRβ-Cre mice were crossed with insulin receptor ‘floxed’ mice to create progeny with mural cell deletion of the insulin receptor (PIR-/-). In-vivo developmental angiogenesis was characterised in the postnatal retina. PIR-/- showed increased sprouting and excessive vascular density in venous regions, resembling some features of diabetic retinopathy. Abnormal vascular structure in PIR-/- was associated with reduced angiopoietin 1 (Ang1) secretion in pericytes and changes to endothelial Tie2 activation and angiopoietin 2 (Ang2) expression, indicating disturbed pericyte-endothelial crosstalk in PIR-/-. Metabolic phenotyping of adult PIR-/- mice revealed whole-body insulin resistance, lipodystrophy and a failure in adipose tissue expansion. Interestingly, vascularity and Ang2 expression are also altered in adipose tissue in PIR-/-, potentially linking both observations to a common pathway. Deletion of the insulin receptor in pericytes modulates angiogenesis and whole-body glucose and lipid metabolism potentially via a common pathway, involving pericyte-endothelial communication via angiopoietins and Tie2 signalling.