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J. Hua, K. I. Guerin, J. Chen, P. Sapieha, A. Stahl, K. Connor, N. M. Krah, R. J. Dennison, M. R. Seaward, L. E. H. Smith; Resveratrol Inhibits Pathological Angiogenesis in the Vldlr Knockout Mouse Model of Retinal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3345.
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Subretinal pathological neovascularization (NV) is the hallmark of wet age-related macular degeneration and other ocular diseases such as juxafoveal telangiectasia. Mice lacking the very low density lipoprotein receptor (VLDLR -/-) mimic these human ocular phenotypes and are a suitable model for studying NV. Resveratrol is a natural dietary polyphenol compound extacted from plants, and reported to inhibit tumor angiogenesis in vivo via oral administration. We investigated the anti-angiogenic effects of oral resveratrol treatment on ocular NV in VLDLR -/- mice, to evaluate its therapeutic potential.
From postnatal day 10 (P10) to P30 (early intervention), VLDLR -/- pups were gavaged daily with resveratrol at 1g/kg bodyweight. Littermate controls received an identical volume of vehicle. In a second experimental paradigm, P21 mice were fed with 2.4g/kg resveratrol for 39 days (late intervention). At P30 or P60, respectively, retinas were flat-mounted to assess the subretinal NV. RNA and protein were extracted from the retinas for RT-qPCR, Western Blot and ELISA. Aortas of VLDLR -/- mice were isolated for an aortic ring assay with or without resveratrol treatment.Results: The pathological NV in VLDLR -/- originates in the deep vascular plexus around P15 and progressively invades the photoreceptor layer of retina towards the subretinal space. mRNA and protein analysis showed significant up-regulation of bFGF in the retinas of both P30 and P60 VLDLR -/- mice. Both early and late interventions with resveratrol significantly reduced the number of abnormal subretinal vessel sprouts in the VLDLR -/- mice (early
Oral intake of resveratrol strongly reduces the number of abnormal subretinal vessels in VLDLR -/- mice, indicating that resveratrol is a promising candidate for treatment of ocular angiogenic diseases.
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