YAP is critical to inflammation, endothelial-mesenchymal transition and subretinal fibrosis in experimental choroidal neovascularization.
YAP is critical to inflammation, endothelial-mesenchymal transition and subretinal fibrosis in experimental choroidal neovascularization.
复制标题
YAP 对于实验性脉络膜新生血管形成中的炎症、内皮间质转化和视网膜下纤维化至关重要。
DOI：
10.1016/j.yexcr.2022.113221
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发表时间：
2022
影响因子：
3.7
通讯作者：
Yifan Feng
中科院分区：
文献类型：
--
作者：
Xi Yang;Rong Zou;Xiaochan Dai;Xinyuan Wu;Fei Yuan;Yifan Feng
视网膜下纤维化是新生血管性年龄相关性黄斑变性（neovascular age-related macular degeneration，nAMD）的最后阶段，可导致视网膜的局部损伤和不可逆的视力丧失。最近，内皮-间充质转化（EndoMT）被认为是视网膜下纤维化中肌成纤维细胞的最重要来源之一，尽管其基础分子机制仍不清楚。本研究通过一系列实验来验证Yes相关蛋白（雅普）可能参与EndoMT和视网膜下纤维化的假说。我们证明了转化生长因子（TGF）-β2刺激通过增加活性氧（ROS）水平诱导人脐静脉内皮细胞（HUVECs）中的雅普去磷酸化（活化）和核转录。此外，通过ROS清除或雅普敲低，HUVEC中TGF-β2介导的EndoMT和促炎细胞因子的产生减少。此外，在小鼠激光诱导的脉络膜新生血管（CNV）模型中，玻璃体内给予靶向雅普的小干扰RNA显著减轻了视网膜下纤维化的严重程度。我们的研究结果为雅普对EndoMT过程的未知作用提供了新的见解，并揭示了雅普作为抑制CNV相关视网膜下纤维化和保护视力的潜在靶点。
Subretinal fibrosis causes local damage to the retina and irreversible vision loss, as the final stage of neovascular age-related macular degeneration (nAMD). More recently, the endothelial-to-mesenchymal transition (EndoMT) has been considered one of the most significant sources of myofibroblasts in subretinal fibrosis, though the underpinning molecular mechanisms remain unclear. In this study, a series of experiments were performed to test the hypothesis that Yes-associated protein (YAP) may be involved in EndoMT and subretinal fibrosis. We demonstrated that transforming growth factor (TGF)-β2 stimulation induces YAP dephosphorylation (activated) and nuclear transcription in human umbilical vein endothelial cells (HUVECs) by increasing reactive oxygen species (ROS) levels. Moreover, TGF-β2-mediated EndoMT and proinflammatory cytokine production in HUVECs were reduced by ROS clearance or YAP knockdown. Furthermore, the severity of subretinal fibrosis was markedly relieved by intravitreal administration of a small interfering RNA targeting YAP in the mouse laser-induced choroidal neovascularization (CNV) model. Our findings provide novel insights into a previously unknown effect of YAP on the EndoMT process and reveal YAP as a potential target for suppressing CNV-related subretinal fibrosis and protect vision.