Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy

Abstract

Background: Oxidative stress (OS) plays a central role in diabetic retinopathy (DR), triggering expression and release of vascular endothelial growth factor (VEGF), the increase of which leads to deleterious vascular changes. We tested the hypothesis that OS-stimulated VEGF induces its own expression with an autocrine mechanism. Methods: MIO-M1 cells and ex vivo mouse retinal explants were treated with OS, with exogenous VEGF or with conditioned media (CM) from OS-stressed cultures. Results: Both in MIO-M1 cells and in retinal explants, OS or exogenous VEGF induced a significant increase of VEGF mRNA, which was abolished by VEGF receptor 2 (VEGFR-2) inhibition. OS also caused VEGF release. In MIO-M1 cells, CM induced VEGF expression, which was abolished by a VEGFR-2 inhibitor. Moreover, the OS-induced increase of VEGF mRNA was abolished by a nuclear factor erythroid 2-related factor 2 (Nrf2) blocker, while the effect of exo-VEGF resulted Nrf2-independent. Finally, both the exo-VEGF- and the OS-induced increase of VEGF expression were blocked by a hypoxia-inducible factor-1 inhibitor. Conclusions: These results are consistent with the existence of a retinal VEGF autocrine loop triggered by OS. This mechanism may significantly contribute to the maintenance of elevated VEGF levels and therefore it may be of central importance for the onset and development of DR.

A Nature-Inspired Nrf2 Activator Protects Retinal Explants from Oxidative Stress and Neurodegeneration

“…Our results show no activation of Nrf2 nuclear translocation or increased expression of antioxidant enzymes in explants incubated for 24 h under OS. This is not entirely consistent with our previous data indicating an increase of Nrf2, NQO1, and HO-1 mRNA expression in retinal explants after 12 or 24 h OS [ 37 , 43 ]. This discrepancy may be explained considering that, although OS is maintained for 24 h in all cases, the OS/2d retinal explants of the present study have undergone a 24 h pre-treatment with basal culture medium.…”

“…The culture medium was changed every day. According to our previous findings, these culture parameters ensure the maintenance of the retinal microarchitecture and neurochemical characteristics [ 37 , 41 , 42 , 43 ].…”

Long non‐coding ribonucleic acid urothelial carcinoma‐associated 1 promotes high glucose‐induced human retinal endothelial cells angiogenesis through regulating micro‐ribonucleic acid‐624‐3p/vascular endothelial growth factor C

“…It has been shown that expression and release of VEGF triggers deleterious vascular changes and leads to DR 41 . Clinical trial data showed that the improvement rates in the subgroup of patients with moderately severe or severe non‐proliferative DR were greatly improved by inhibiting VEGF 42 .…”

Neovascular Macular Degeneration: A Review of Etiology, Risk Factors, and Recent Advances in Research and Therapy

“…Oxidative stress triggers many other pathways, with the autocrine signaling and upregulation of VEGF being no exception. Oxidative stress and ROS synergize with other pathways (NLRP3, complement cascade, Ang 2, hypoxia), further promoting angiogenesis and progression of nvAMD [ 173 , 174 ]. Once VEGF-A binds to the receptor, several signaling pathways are activated: (1) the Mitogen-activated protein kinase- (MAPK-) p38 signaling pathway, where the effector heat shock protein (HSP27) reorganizes actin [ 175 ], (2) the phosphatidylinositol 3-kinase- (PI3K-) AKT protein kinase B pathway, promoting the formation of nitric oxide [ 176 , 177 ], and (3) the phospholipase C gamma (PLC γ ) releasing intracellular calcium, promoting prostaglandin production, increasing vascular permeability [ 178 , 179 ].…”