Resveratrol Inhibits Hypoxia-Induced Vascular Endothelial Growth Factor Expression and Pathological Neovascularization
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Purpose: To investigate the effects of resveratrol on the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelialgrowth factor (VEGF) in human adult retinal pigment epithelial (ARPE-19) cells, and on experimental choroidal neovascularization(CNV) in mice. Materials and Methods: ARPE-19 cells were treated with different concentrations of resveratrol and then incubated under hypoxicconditions with subsequent evaluation of cell viability, expression of HIF-1α, and expression of VEGF. The effects of resveratrolon the synthesis and degradation of hypoxia-induced HIF-1α were evaluated using inhibitors of the PI3K/Akt/mTOR and theubiquitin proteasome pathways. In animal studies, CNV lesions were induced in C57BL/6 mice by laser photocoagulation. After 7days of oral administration of resveratrol or vehicle, which began one day after CNV induction, image analysis was used to measureCNV areas on choroidal flat mounts stained with isolectin IB4. Results: In ARPE-19 cells, resveratrol significantly inhibited HIF-1α and VEGF in a dose-dependent manner, by blocking thePI3K/Akt/mTOR signaling pathway and by promoting proteasomal HIF-1α degradation. In mice experiments, orally administeredresveratrol significantly inhibited CNV growth in a dose-dependent manner. Conclusion: Resveratrol may have therapeutic value in the management of diseases involving pathological neovascularization.
Abstract
Purpose: To investigate the effects of resveratrol on the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelialgrowth factor (VEGF) in human adult retinal pigment epithelial (ARPE-19) cells, and on experimental choroidal neovascularization(CNV) in mice. Materials and Methods: ARPE-19 cells were treated with different concentrations of resveratrol and then incubated under hypoxicconditions with subsequent evaluation of cell viability, expression of HIF-1α, and expression of VEGF. The effects of resveratrolon the synthesis and degradation of hypoxia-induced HIF-1α were evaluated using inhibitors of the PI3K/Akt/mTOR and theubiquitin proteasome pathways. In animal studies, CNV lesions were induced in C57BL/6 mice by laser photocoagulation. After 7days of oral administration of resveratrol or vehicle, which began one day after CNV induction, image analysis was used to measureCNV areas on choroidal flat mounts stained with isolectin IB4. Results: In ARPE-19 cells, resveratrol significantly inhibited HIF-1α and VEGF in a dose-dependent manner, by blocking thePI3K/Akt/mTOR signaling pathway and by promoting proteasomal HIF-1α degradation. In mice experiments, orally administeredresveratrol significantly inhibited CNV growth in a dose-dependent manner. Conclusion: Resveratrol may have therapeutic value in the management of diseases involving pathological neovascularization.
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