PDF(Sci-hub)
Abstract：
Retinopathies remain major causes of visual impairment in diabetic patients and premature infants. Introduction of anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) has transformed therapy for these proliferative retinopathies. However, limitations associated with anti-VEGF medications require to unravel new pathways of vessel growth to identify potential drug targets. Here, we investigated the role of Wnt/Frizzled-7 (Fzd7) pathway in a mouse model of oxygen-induced retinopathy (OIR). Using transgenic mice, which enabled endothelium-specific and time-specific Fzd7 deletion, we demonstrated that Fzd7 controls both vaso-obliteration and neovascular phases (NV). Deletion of Fzd7 at P12, after the ischemic phase of OIR, prevented formation of aberrant neovessels into the vitreous by suppressing proliferation of endothelial cells (EC) in tufts. Next we validated in vitro two Frd7 blocking strategies: a monoclonal antibody (mAbFzd7) against Fzd7 and a soluble Fzd7 receptor (CRD). In vivo a single intravitreal microinjection of mAbFzd7 or CRD significantly attenuated retinal neovascularization (NV) in mice with OIR. Molecular analysis revealed that Fzd7 may act through the activation of Wnt/β-catenin and Jagged1 expression to control EC proliferation in extra-retinal neovessels. We identified Fzd7/β-catenin signaling as new regulator of pathological retinal NV. Fzd7 appears to be a potent pharmacological target to prevent or treat aberrant angiogenesis of ischemic retinopathies.
摘要：
视网膜病变仍然是糖尿病患者和早产儿视力障碍的主要原因。靶向血管内皮生长因子（VEGF）的抗血管生成药物的引入已经改变了这些增生性视网膜病的治疗方法。然而,与抗VEGF药物相关的局限性需要解开血管生长的新途径,以确定潜在的药物靶点.这里,我们研究了Wnt/Frizzled-7(Fzd7)通路在氧诱导视网膜病变(OIR)小鼠模型中的作用.使用转基因小鼠，这使得内皮特异性和时间特异性Fzd7缺失，我们证明Fzd7控制血管闭塞和新生血管期(NV).在OIR缺血期后，P12时Fzd7的缺失，通过抑制簇绒中内皮细胞（EC）的增殖来防止异常新生血管进入玻璃体。接下来,我们在体外验证了两种Frd7阻断策略:针对Fzd7的单克隆抗体(mAbFzd7)和可溶性Fzd7受体(CRD)。在体内,单次玻璃体内显微注射mAbFzd7或CRD显著减弱OIR小鼠的视网膜新生血管形成(NV)。分子分析表明，Fzd7可能通过激活Wnt/β-catenin和Jagged1表达来控制视网膜外新生血管中的EC增殖。我们确定Fzd7/β-catenin信号是病理性视网膜NV的新调节因子。Fzd7似乎是预防或治疗缺血性视网膜病变的异常血管生成的有效药理学靶标。
