Angiopoietin 2 Induces Pericyte Apoptosis via α3β1 Integrin Signaling in Diabetic Retinopathy

Abstract

Purpose: Pericyte loss is an early characteristic change in diabetic retinopathy. Despite accumulating evidences that hyperglycemia induced angiopoietin 2 (Ang2) has a central role in pericyte loss, the precise molecular mechanism has not been elucidated. This study was to investigate the role of Ang2 in pericyte loss in diabetic retinopathy.

Methods: STZ-induced diabetic mice retina was digested and capillary pericytes were quantified. Ang2 ELISA and qRT-PCR were performed in diabetic retina and endothelial cells, respectively. MTT assay was performed to evaluate cell viability under high glucose and Ang2 treatment in pericyte. Apoptosis was analyzed using FACS. Integrin and Tie-2 receptor expression was evaluated using qRT-PCR and Western blot. The effect of integrin blocker to Ang2 induced apoptotic pathway was evaluated using Western blot. Integrin blocker was also intravitreously injected in Ang2 injected mice.

Results: The number of retinal capillary pericyte was decreased in the STZ-induced diabetic mice retina. Ang2 was increased in diabetic retina and the source of Ang2 was endothelial cells. Ang2 played synergistic role in pericyte apoptosis via p53 pathway under high glucose condition. Integrin, not Tie-2, was essential for Ang2 induced pericyte apoptosis under high glucose as an Ang2 receptor. Ang2 induced pericyte apoptosis was inhibited by suppression of integrin α3β1. Intravitreal injection of integrin α3β1 blocker effectively prevented Ang2 induced pericyte loss in retina.

Conclusions: Ang2 induced pericyte apoptosis via integrin α3β1 in diabetic retinopathy. Our data suggest that Ang2 and integrin α3β1 could be potential therapeutic target to prevent pericyte loss in early diabetic retinopathy.

Keywords: 499 diabetic retinopathy