沉默YAP通过Hippo/MAPK通路减轻脉络膜新生血管中周细胞-肌成纤维细胞转化和视网膜下纤维化

Abstract

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.