VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases

Abstract

Müller glia (MG) are major retinal supporting cells that participate in retinal metabolism, function, maintenance, and protection. During the pathogenesis of diabetic retinopathy (DR), a neurovascular disease and a leading cause of blindness, MG modulate vascular function and neuronal integrity by regulating the production of angiogenic and trophic factors. In this article, I will (1) briefly summarize our work on delineating the role and mechanism of MG-modulated vascular function through the production of vascular endothelial growth factor (VEGF) and on investigating VEGF signaling-mediated MG viability and neural protection in diabetic animal models, (2) explore the relationship among VEGF and neurotrophins in protecting Müller cells in in vitro models of diabetes and hypoxia and its potential implication to neuroprotection in DR and hypoxic retinal diseases, and (3) discuss the relevance of our work to the effectiveness and safety of long-term anti-VEGF therapies, a widely used strategy to combat DR, diabetic macular edema, neovascular age-related macular degeneration, retinopathy of prematurity, and other hypoxic retinal vascular disorders.

Keywords: AMD; BRB breakdown; DR; Hypoxia; Müller glia; Neuroprotection; Neurotrophin; ROP; VEGF.

Figure 1

Schematic diagram for potential roles of MG-derived VEGF in DR. Phenotypical changes are in italic. Potential functions with no direct experimental and clinical data are indicated with a question marker. MG modulate vascular function and neuronal integrity through the production and signaling of VEGF.

Figure 2

Potential mechanism of VEGF signaling-mediated MG viability and neuroprotection in DR and hypoxia. A, B: Effect of VEGF, BDNF, and/or GDNF on rMC1 cell viability (relative cellular density after 22 h) in high glucose (A) or hypoxia (B)(100 mM CoCl₂). NG: normal glucose (5 mM). HG: high glucose (25 mM) media. Growth factor supplement: 0.24 ng/mL. ***: p<0.001. **: p<0.01. **: p<0.05. Error bar: SD. p-values: represent pairwise comparison with vehicle by t-test. C: Putative mechanism of VEGF/VEGFR2 signaling-mediated MG viability and its role in neuroprotection in DR and hypoxic retinal diseases. Solid arrows: with supporting data. Broken arrows: direct experimental and clinical data are not available.