Resveratrol inhibits hypoxia-induced vascular endothelial growth factor expression and choroidal neovascularization

Abstract

Purpose. To investigate the effects of resveratrol on the expression of hypoxia–inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in human adult retinal pigment epithelial (ARPE) cells, and on experimental choroidal neovascularization (CNV) in mice. Methods. Human retinal pigment epithelial cells (ARPE-19) were treated with different concentrations of resveratrol and incubated under hypoxic conditions with subsequent evaluation of cell viability, expression of HIF-1α, and expression of VEGF. In the same cells, the effects of resveratrol on the synthesis and degradation of hypoxia-induced HIF-1α were evaluated using inhibitors of the PI3K/Akt/mTOR and the ubiquitin proteasome pathways. In animal studies, CNV lesions were induced in C57BL/6 mice by laser photocoagulation. After 7 days of oral administration of resveratrol or vehicle, which began one day after CNV induction, image analysis was used to measure CNV areas on choroidal flat mounts stained with isolectin IB4. Results. In ARPE-19 cells, resveratrol significantly inhibited hypoxia-induced increases of HIF-1α and VEGF in a dose-dependent manner, by blocking the PI3K/Akt/mTOR signaling pathway and by promoting proteasomal HIF-1α degradation. In mice experiments, orally administered resveratrol significantly inhibited CNV growth in a dose-dependent manner. Conclusions. Resveratrol effectively inhibited the accumulation of hypoxia-induced HIF-1α and VEGF in ARPE-19 cells, and inhibited the progression of experimental CNV in mice, suggesting resveratrol’s therapeutic value in the management of neovascular AMD.