Pericyte insulin receptors modulate retinal vascular remodeling and endothelial angiopoietin signaling

Endocrinology. 2021 Aug 30:bqab182. doi: 10.1210/endocr/bqab182. Online ahead of print.ABSTRACTPericytes regulate vascular development, stability and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFR β-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited peri-venous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers. Pericyte coverage of capillaries was unaltered in peri-venous and peri-arterial plexi and no differences in vascular regression or endothelial proliferation were apparent. Isolated brain pericytes from PIRKO had decreased angiopoietin-1 mRNA, whereas retinal and lung angiopoietin-2 mRNA was increased. Endothelial phospho-Tie2 staining was diminished and FoxO1 was more frequently nuclear localized in the peri-venous plexus of PIRKO, in keeping with reduced angiopoietin-Tie2 signaling. Silencing of Insr in human brain pericytes led to reduced insulin-stimulated angiopoietin-1 secretion, and conditioned media from these cells was less able to induce Tie2 phosphorylation in human endothelial cells. Hence, insulin signaling in pericytes promotes angiopoietin-1 secretion and endothelial Tie2 signaling and perturbation of this leads to excessive vascular sprouting and venous plexus abnormalities. This phenotype mimic...

Source: Endocrinology - August 30, 2021 Category: Endocrinology Authors: Nele Warmke Fiona Platt Alexander F Bruns Claire H Ozber Natalie J Haywood Yilizila Abudushalamu Charles Slater Victoria Palin Piruthivi Sukumar Stephen B Wheatcroft Nadira Y Yuldasheva Mark T Kearney Kathryn J Griffin Richard M Cubbon Source Type: research