Silencing of YAP attenuates pericyte‐myofibroblast transition and subretinal fibrosis in experimental model of choroidal neovascularization
Silencing of YAP attenuates pericyte‐myofibroblast transition and subretinal fibrosis in experimental model of choroidal neovascularization
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DOI：
10.1002/cbin.11809
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发表时间：
2022-04
影响因子：
3.9
通讯作者：
Ya-Hui Xu;Yi-Fan Feng;Rong Zou;Fei Yuan;Yuan-Zhi Yuan-Yuan-Zhi-Yuan-2153108419
中科院分区：
文献类型：
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作者：
Ya-Hui Xu;Yi-Fan Feng;Rong Zou;Fei Yuan;Yuan-Zhi Yuan-Yuan-Zhi-Yuan-2153108419
年龄相关性黄斑变性（AMD）是老年人不可逆视力丧失的主要原因。脉络膜新生血管（CNV）后的视网膜下纤维化是湿性AMD晚期的重要特征，被认为是对抗VEGF药物反应不完全的原因之一。最近的研究表明，周细胞-肌成纤维细胞转化（PMT）是一个重要的病理过程，涉及各种器官的纤维化疾病。然而，PMT在CNV视网膜下纤维化中的具体作用和机制尚不清楚。已经清楚的是，Hippo通路沿着其下游效应子Yes相关蛋白（雅普）在上皮和内皮肌成纤维细胞发育中起重要作用。因此，我们推测雅普是否参与了周细胞的PMT并促进CNV的纤维化。在这项研究中，在C57 BL/6 J（B6）小鼠中通过激光光凝诱导实验性CNV，在激光损伤眼的视网膜色素上皮/脉络膜/巩膜组织中检测到异常的雅普过表达。雅普基因敲低可降低体外培养的人视网膜微血管周细胞的增殖、迁移和分化。它还减少了体内激光诱导的CNV的视网膜下纤维化。此外，通过对周细胞条件培养基（PC-CM）进行基于蛋白质组学的分析和生物信息学分析，我们发现Hippo/雅普和MAPK/Erk之间的串扰参与了缺氧周细胞中细丝蛋白A的表达。这些结果表明，Hippo/雅普和MAPK/Erk连接在一起，介导周细胞增殖，迁移以及分化，这可能体现了潜在的意义，用于治疗与CNV相关的疾病。
Age‐related macular degeneration (AMD) is the main reason of irreversible vision loss in the elderly. The subretinal fibrosis subsequent to choroidal neovascularization (CNV) is an important feature in the late stage of wet AMD and is considered to be one reason for incomplete response to anti‐VEGF drugs. Recent studies have shown that pericyte‐myofibroblast transition (PMT) is an important pathological process involving fibrotic diseases of various organs. However, the specific role and mechanism of PMT in the subretinal fibrosis of CNV have not been clarified. It has been clear that the Hippo pathway along with its downstream effector Yes‐associated protein (YAP) plays an important role in both epithelial and endothelial myofibroblast development. Therefore, we speculate whether YAP participates in PMT of pericytes and promotes fibrosis of CNV. In this study, experimental CNV was induced by laser photocoagulation in C57BL/6J (B6) mice, and aberrant YAP overexpression was detected in the retinal pigment epithelial/choroid/sclera tissues of the laser‐injured eyes. YAP knockdown reduced the proliferation, migration, and differentiation of human retinal microvascular pericytes in vitro. It also reduced subretinal fibrosis of laser‐induced CNV in vivo. Moreover, by proteomics‐based analysis of pericyte conditioned medium (PC‐CM) and bioinformatic analyses, we identified that the crosstalk between Hippo/YAP and MAPK/Erk was involved in expression of filamin A in hypoxic pericytes. These findings suggest that Hippo/YAP and MAPK/Erk are linked together to mediate pericyte proliferation, migration as well as differentiation, which may embody potential implications for treatment in diseases related to CNV.