A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy.
A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy.
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Norrin/Wnt替代抗体刺激内皮细胞屏障功能并挽救视网膜病变。
DOI：
10.15252/emmm.202113977
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发表时间：
2021-07-07
影响因子：
11.1
通讯作者：
Angers S
中科院分区：
文献类型：
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作者：
Chidiac R;Abedin M;Macleod G;Yang A;Thibeault PE;Blazer LL;Adams JJ;Zhang L;Roehrich H;Jo HN;Seshagiri S;Sidhu SS;Junge HJ;Angers S
FZD 4：LRP 5：TSPAN 12受体复合物被视网膜内皮细胞中分泌的蛋白Norrin激活，并导致发育期间血视网膜屏障的β连环蛋白依赖性形成及其在成人中的稳态。已经在几种导致视网膜血管形成不足和失明的先天性疾病中鉴定出破坏Norrin信号传导的突变。在这里，我们开发了F4L5.13，这是一种四价抗体，旨在以触发β连环蛋白信号传导的方式诱导FZD 4和LRP 5接近。用F4L5.13处理培养的内皮细胞部分地通过促进连接蛋白的表面表达来挽救VEGF诱导的渗透性。用F4L5.13治疗Tspan 12 −/−小鼠恢复了视网膜血管生成和屏障功能。F4L5.13治疗还显著使氧诱导的视网膜病变模型中的新血管形成正常化，揭示了以异常血管生成和/或屏障功能障碍为特征的疾病的新治疗策略。本研究报告了一种FZD 4：LRP 5抗体激动剂（F4L5.13），可激活内皮细胞中的β连环蛋白信号传导。F4L5.13在动物模型中通过使缺陷的视网膜血管生成和屏障功能正常化而显示出功效，为眼部疾病提供了新的治疗策略。
The FZD4:LRP5:TSPAN12 receptor complex is activated by the secreted protein Norrin in retinal endothelial cells and leads to βcatenin‐dependent formation of the blood–retina–barrier during development and its homeostasis in adults. Mutations disrupting Norrin signaling have been identified in several congenital diseases leading to hypovascularization of the retina and blindness. Here, we developed F4L5.13, a tetravalent antibody designed to induce FZD4 and LRP5 proximity in such a way as to trigger βcatenin signaling. Treatment of cultured endothelial cells with F4L5.13 rescued permeability induced by VEGF in part by promoting surface expression of junction proteins. Treatment of Tspan12 −/− mice with F4L5.13 restored retinal angiogenesis and barrier function. F4L5.13 treatment also significantly normalized neovascularization in an oxygen‐induced retinopathy model revealing a novel therapeutic strategy for diseases characterized by abnormal angiogenesis and/or barrier dysfunction. This study reports a FZD4:LRP5 antibody agonist (F4L5.13) that activates βcatenin signaling in endothelial cells. F4L5.13 shows efficacy in animal models by normalizing defective retinal angiogenesis and barrier function, providing a novel therapeutic strategy for eye diseases.