Resveratrol Inhibits Retinal Neovascularization in Vldlr-/- mouse

Abstract

Purpose: : MacTel (idiopathic parafoveal telangiectasia) is a vision-threatening retinal vascular disease characterized by abnormal retinal neovascularization in the perimacular region and photoreceptor degeneration. The pathogenesis of MacTel is not yet understood and there is no recognized treatment. Mice lacking the very low density lipoprotein receptor (Vldlr-/-) have subretinal neovascularization mimicking MacTel. We evaluated the therapeutic potential of the plant polyphenol resveratrol in the Vldlr-/- mouse.

Methods: : Vldlr-/- mice were fed diets supplemented with resveratrol from P21 to P60 or from P10 to P30. The number of subretinal neovascular lesions was quantified on retinal wholemounts. Effects of resveratrol were assessed in vitro with aortic ring and cell migration assays, as well as with western blot analysis. The expression of Vegf and Gfap in whole retina and laser-captured samples from retinal layers within and outside neovascular lesions from Vldlr-/- and wild type (WT) mice was assessed with qRT-PCR.

Results: : Pathologic neovascularization in Vldlr-/- retina develops in the outer nuclear layer at P15, with a focal upregulation of Vegf and Gfap in the photoreceptors and inner retina, respectively. Resveratrol significantly reduces the number of subretinal lesions in the Vldlr-/- retina (102.1±4.9 lesions per Vldlr-/- retina, n=18, 166.7±11.9 lesions per WT retina, n=15, p<0.00001), and is associated with a marked reduction in both Vegf and Gfap mRNA expression, as well as a trend toward increased rhodopsin expression. Resveratrol treatment in vitro significantly decreases endothelial cell sprouting in WT and Vldlr-/- aortic ring explants and VEGF-stimulated endothelial migration via reduced ERK1/2 phosphorylation.

Conclusions: : Oral administration of resveratrol significantly reduces the number of abnormal subretinal neovessels in the Vldlr-/- mouse by inhibiting VEGF expression and activation of endothelial cells. This study suggests that resveratrol may be a potential treatment for patients with MacTel and similar neovascular retinal conditions.

Keywords: retinal neovascularization • retinal development • vascular endothelial growth factor