The role of pericyte insulin signalling

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.