Retinal angiogenesis is a critical process for normal retinal function. However, uncontrolled angiogenesis can lead to pathological neovascularization (NV), which is closely related to most irreversible blindness-causing retinal diseases. Understanding the molecular basis behind pathological NV is important for the treatment of related diseases. Twist-related protein 1 (TWIST1) is a well-known transcription factor and principal inducer of epithelial-mesenchymal transition (EMT) in many human cancers. Our previous study showed that Twist1 expression is elevated in pathological retinal NV. To date, however, the role of TWIST1 in retinal pathological angiogenesis remains to be elucidated. To study the role of TWIST1 in pathological retinal NV and identify specific molecular targets for antagonizing pathological NV, we generated an inducible vascular endothelial cell (EC)-specific Twist1 transgenic mouse model ( Tg-Twist1 iEC+ ). Whole-mount retinas from Tg-Twist1 iEC+ mice showed retarded vascular progression and increased vascular density in the front end of the growing retinal vasculature, as well as aneurysm-like pathological retinal NV. Furthermore, overexpression of Twist1 in the ECs promoted cell proliferation but disturbed cell polarity, thus leading to uncontrolled retinal angiogenesis. TWIST1 promoted pathological NV by activating the Wnt/β-catenin signaling pathway and inducing the expression of NV formation-related genes, thereby acting as a 'valve' in the regulation of pathological angiogenesis. This study identified the critical role of TWIST1 in retinal pathological NV, thus providing a potential therapeutic target for pathological NV.
视网膜新生血管生成是视网膜正常行使功能的关键过程。然而，不受控制的血管生成会导致病理性新生血管（NV），而病理性NV与大多数不可逆的致盲性视网膜疾病密切相关。了解病理性NV背后的分子基础对于相关疾病的治疗具有重要意义。Twist相关蛋白1（TWIST1）是一种转录因子并且是上皮间充质转变（EMT）过程的主要诱导因子。我们之前的研究表明， Twist1在病理性视网膜NV生成期间表达升高。然而，迄今为止， Twist1在视网膜病理性血管生成中的作用仍有待阐明。为了研究 TWIST1在病理性NV中的作用并鉴定可用于对抗病理性NV的特异性分子标志物，我们构建了可诱导的血管内皮细胞（EC）特异性 Twist1基因过表达的转基因小鼠模型（ Tg-Twist1 iEC + ）。视网膜铺片结果显示来自 Tg-Twist1 iEC + 小鼠的视网膜新生血管形成滞后，血管生成前端血管密度增加，并且出现动脉瘤样病理性NV。进一步地，我们发现，EC中 Twist1的过表达促进了细胞增殖，但破坏了细胞极性，从而导致不受控制的视网膜新生血管生成。从机制上讲，TWIST1通过激活Wnt/β-catenin信号通路并诱导NV形成相关基因的表达来促进NV，从而在病理性血管生成的调节过程中发挥"阀门"的作用。该研究确定了TWIST1在视网膜病理性NV中的关键作用，从而为病理性NV提供了潜在的治疗靶点。.
Keywords: Molecular markers; Mouse model; Pathological angiogenesis; Retinal neovascularization; TWIST1.