Department of Physiology, University of Oklahoma, Health Sciences Center, Oklahoma City, Oklahoma, USA.
Invest Ophthalmol Vis Sci. 2013 Jan 7;54(1):141-54. doi: 10.1167/iovs.12-10281.
Choroidal neovascularization (CNV) is a severe complication of AMD. The Wnt signaling pathway has been shown to mediate angiogenesis. The purpose of this study was to investigate the pathogenic role of the Wnt pathway in CNV and explore the therapeutic potential of a novel Wnt signaling inhibitor in CNV.
Adult rats and mice were photocoagulated using diode laser to induce CNV. On the same day, the animals were intravitreally injected with a monoclonal antibody (Mab2F1) blocking LRP6 or nonspecific mouse IgG. The Wnt signaling activation and target gene expression in the eyecup were determined by Western blot analysis. Fundus angiography was used to examine leakage from the laser lesion. CNV areas were measured on choroidal flatmount using FITC-dextran.
Levels of Wnt pathway components and Wnt target gene expression were elevated in both laser-induced CNV rat and mouse eyecups, suggesting activation of the Wnt pathway. Significant suppression of Wnt signaling was observed in the Mab2F1 treatment group. Mab2F1 decreased vascular leakage from CNV lesions and reduced the neovascular area in laser-induced CNV rats. Mab2F1 inhibited the hypoxia-induced activation of Wnt signaling in cultured RPE cells. Mab2F1 also ameliorated retinal inflammation and vascular leakage in the eyecups of very low-density lipoprotein receptor knockout mice, a model of subretinal neovascularization.
The Wnt pathway is activated in the laser-induced CNV models and plays a pathogenic role in CNV. Blockade of Wnt signaling using an anti-LRP6 antibody has therapeutic potential in CNV.
脉络膜新生血管（CNV）是 AMD 的严重并发症。Wnt 信号通路已被证明可介导血管生成。本研究旨在探讨 Wnt 通路在 CNV 中的致病作用，并探索新型 Wnt 信号抑制剂在 CNV 中的治疗潜力。
使用二极管激光对成年大鼠和小鼠进行光凝以诱导 CNV。当天，通过玻璃体腔注射抗 LRP6 单克隆抗体（Mab2F1）或非特异性小鼠 IgG 对动物进行处理。通过 Western blot 分析检测眼杯中 Wnt 信号的激活和靶基因表达。通过眼底血管造影检查激光损伤处的渗漏。使用 FITC-葡聚糖在脉络膜平面上测量 CNV 面积。
激光诱导的大鼠和小鼠眼杯中的 Wnt 通路成分和 Wnt 靶基因表达水平升高，表明 Wnt 通路被激活。在 Mab2F1 治疗组观察到 Wnt 信号的显著抑制。Mab2F1 减少了 CNV 病变中的血管渗漏，并减少了激光诱导的 CNV 大鼠中的新生血管面积。Mab2F1 抑制了培养的 RPE 细胞中缺氧诱导的 Wnt 信号激活。Mab2F1 还改善了极低密度脂蛋白受体敲除小鼠的眼杯中的视网膜炎症和血管渗漏，该模型为脉络膜下新生血管形成。
Wnt 通路在激光诱导的 CNV 模型中被激活，并在 CNV 中发挥致病作用。使用抗 LRP6 抗体阻断 Wnt 信号具有治疗 CNV 的潜力。
