Connexin 43 (Cx43) regulates high-glucose-induced retinal endothelial cell angiogenesis and retinal neovascularization

Abstract

Diabetic retinopathy (DR) is an important microvascular complication of type 1 and type 2 diabetes mellitus (DM) and a major cause of blindness. Retinal neovascularization plays a critical role in the proliferative DR. In this study, high glucose-induced connexin 43 (Cx43) expression in human retinal endothelial cells (hRECs) in a dose-dependent manner. Compared with hRECs under normal culture conditions, high-glucose (HG)-stimulated hRECs showed promoted tubule formation, increased ROS release, and elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), vascular endothelial growth factor A (VEGFA), and intercellular adhesion molecule 1 (ICAM-1) in the culture medium. HG-induced alterations were further magnified after <i>Cx43</i> overexpression, whereas partially eliminated after <i>Cx43</i> knockdown. Finally, in the DR mouse model, impaired retinal structure, increased CD31 expression, and elevated mRNA levels of <i>TNF-α</i>, <i>IL-1β</i>, <i>VEGFA</i>, and <i>ICAM-1</i> were observed; <i>in-vivo Cx43</i> knockdown partially reversed these phenomena. Conclusively, <i>Cx43</i> knockdown could inhibit hREC angiogenesis, therefore improving DR in the mouse model.