Neurovascular cross talk in diabetic retinopathy: Pathophysiological roles and therapeutic implications

Abstract

Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in developed countries, and its prevalence will increase as the global incidence of diabetes grows exponentially. DR begins with an early nonproliferative stage in which retinal blood vessels and neurons degenerate as a consequence of chronic hyperglycemia, resulting in vasoregression and persistent retinal ischemia, metabolic disequilibrium, and inflammation. This is conducive to overcompensatory pathological neovascularization associated with advanced proliferative DR. Although DR is considered a microvascular complication, the retinal microvasculature is intimately associated with and governed by neurons and glia; neurodegeneration, neuroinflammation, and dysregulation of neurovascular cross talk are responsible in part for vascular abnormalities in both early nonproliferative DR and advanced proliferative DR. Neuronal activity directly regulates microvascular dilation and blood flow in the process of neurovascular coupling. Retinal neurons also secrete guidance cues in response to injury, ischemia, or metabolic stress that may either promote or suppress vascular outgrowth, either alleviating or exacerbating DR, contingent on the stage of disease and retinal microenvironment. Neurodegeneration, impaired neurovascular coupling, and dysregulation of neuronal guidance cues are key events in the pathogenesis of DR, and correcting these events may prevent or delay development of advanced DR. The review discusses the mechanisms of neurovascular cross talk and its dysregulation in DR, and their potential therapeutic implications.

Keywords: angiogenesis; metabolism; retinal degeneration.

Copyright © 2016 the American Physiological Society.

Figures

Fig. 1.

Schematic illustration of the ocular vasculature. The outer nuclear layer (ONL) is avascular, relying on the choroidal blood supply. The inner nuclear layer (INL) is vascularized by the deep and intermediate vascular plexuses. The ganglion cell layer (GCL) is vascularized by the intermediate and superficial vascular plexuses. NFL, nerve fiber layer; RPE, retinal pigment epithelium. Adapted from Ref. . Copyright 2016 by Springer. Reprinted with permission.

Fig. 2.

Schematic illustration of the development of proliferative diabetic retinopathy (DR) adapted from Ref. . Nonproliferative DR (NPDR) is characterized by vasoregression, which results in widespread retinal ischemia. In proliferative DR (PDR), compensatory but ultimately pathological neovascularization occurs in response to retinal ischemia. Neovessels are fragile, prone to leakage, and are often misdirected into the vitreous, later forming fibrosed membranes that may lead to tractional detachments of the retina, resulting in blindness.

Fig. 3.

Schematic of SEMA3A and SEMA3E signaling from Refs. and . A: in the diabetic retina potentially reparative neovessels fail to revascularize the ischemic avascular retina and instead form misdirected neovascular tufts, which is regulated in part by semaphorins. B: semaphorins are secreted by hypoxic retinal ganglion cells (RGCs, shown in blue) in the avascular retina. SEMA3A (gray) represses vascular outgrowth by binding receptor Neuropilin-1 (green) on endothelial tip cells and neovascular tufts, whereas SEMA3E (purple) represses vascular outgrowth by binding receptor Plexin-D1 (beige) on tip cells and neovascular tufts.