Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling

Author:

Warmke Nele12,Platt Fiona1,Bruns Alexander F1,Ozber Claire H1,Haywood Natalie J1,Abudushalamu Yilizila1,Slater Charles1,Palin Victoria1,Sukumar Piruthivi1,Wheatcroft Stephen B1ORCID,Yuldasheva Nadira Y1,Kearney Mark T1,Griffin Kathryn J1ORCID,Cubbon Richard M1ORCID

Affiliation:

1. Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK

2. Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany

Abstract

Abstract Pericytes 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 PDGFRβ-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited perivenous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers. Pericyte coverage of capillaries was unaltered in perivenous and periarterial 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 perivenous 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 mimics elements of diabetic retinopathy, and future work should evaluate pericyte insulin signaling in this disease.

Funder

University of Leeds Alumnus Footsteps Fund

British Heart Foundation Clinical Research Training Fellowship

British Heart Foundation Intermediate Clinical Fellowship

Publisher

The Endocrine Society

Subject

Endocrinology

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