Resveratrol Inhibits Pathologic Retinal Neovascularization in Vldlr-/- Mice
Resveratrol Inhibits Pathologic Retinal Neovascularization in Vldlr-/- Mice
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DOI：
10.1167/iovs.10-6496
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发表时间：
2011-04-01
影响因子：
4.4
通讯作者：
Smith, Lois E. H.
中科院分区：
文献类型：
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作者：
Hua, Jing;Guerin, Karen I.;Smith, Lois E. H.
目的。黄斑毛细血管扩张症（MacTel）是一种危害视力的视网膜疾病，发病机制尚不清楚，目前尚无批准的治疗方法。极低密度脂蛋白受体突变小鼠（Vldlr(-/-)）表现出MacTel的关键特征，如视网膜新生血管和光受体变性。在这项研究中，作者评估了白藜芦醇，一种植物多酚，在Vldlr（-/-）小鼠中作为mactel模型的治疗潜力。在出生后(P) 21 ~ P60或P10 ~ P30时口服白藜芦醇治疗Vldlr（-/-）和野生型小鼠。在视网膜平板支架上评估新血管病变的数量，并通过磷酸化ERK1/2、主动脉环和迁移试验的Western blot方法评估白藜芦醇对内皮细胞的作用。在Vldlr（-/-）和野生型视网膜血管生成病变和非病变区域的激光捕获显微解剖视网膜层中评估Vegf和Gfap的表达。从P15开始，Vldlr（-/-）视网膜发生与光感受器中Vegf和内视网膜Gfap局部上调相关的血管病变。在发病前或发病后口服白藜芦醇可减少病变形成。白藜芦醇治疗的Vldlr（-/-）小鼠血管病变的减少与视网膜Vegf转录的抑制有关。白藜芦醇还能降低内皮细胞ERK1/2信号以及内皮细胞的迁移和增殖。此外，在Vldlr（-/-）视网膜中观察到视紫红质mRNA增加的趋势。口服白藜芦醇通过抑制Vegf表达和视网膜内皮细胞的血管生成激活，对Vldlr（-/-）小鼠视网膜新生血管病变具有保护作用。这些结果提示白藜芦醇可能是一种安全有效的干预治疗MacTel患者。（Invest Ophthalmol Vis Sci. 2011;52:2809-28） DOI: 10.1167/iovs.10-6496
PURPOSE. Macular telangiectasia (MacTel) is a vision-threatening retinal disease with unknown pathogenesis and no approved treatment. Very low-density lipoprotein receptor mutant mice (Vldlr(-/-)) exhibit critical features of MacTel such as retinal neovascularization and photoreceptor degeneration. In this study, the authors evaluate the therapeutic potential of resveratrol, a plant polyphenol, in Vldlr(-/-) mice as a model for MacTel.METHODS. Vldlr(-/-) and wild-type mice at postnatal day (P) 21 to P60 or P10 to P30 were treated orally with resveratrol. The number of neovascular lesions was evaluated on retinal flatmounts, and resveratrol effects on endothelial cells were assessed by Western blot for phosphorylated ERK1/2, aortic ring, and migration assays. Vegf and Gfap expression was evaluated in laser-capture microdissected retinal layers of angiogenic lesions and nonlesion areas from Vldlr(-/-) and wild-type retinas.RESULTS. From P15 onward, Vldlr(-/-) retinas develop vascular lesions associated with the local upregulation of Vegf in photoreceptors and Gfap in the inner retina. Oral resveratrol re-duces lesion formation when administered either before or after disease onset. The reduction of vascular lesions in resveratrol-treated Vldlr(-/-) mice is associated with the suppression of retinal Vegf transcription. Resveratrol also reduces endothelial ERK1/2 signaling as well as the migration and proliferation of endothelial cells. Furthermore, a trend toward increased rhodopsin mRNA in Vldlr(-/-) retinas is observed.CONCLUSIONS. Oral administration of resveratrol is protective against retinal neovascular lesions in Vldlr(-/-) mice by inhibiting Vegf expression and angiogenic activation of retinal endothelial cells. These results suggest that resveratrol might be a safe and effective intervention for treating patients with MacTel. (Invest Ophthalmol Vis Sci. 2011;52:2809-2816) DOI: 10.1167/iovs.10-6496