Inactivation of adenosine receptor 2A suppresses endothelial-to-mesenchymal transition and inhibits subretinal fibrosis in mice

作者：Qiuhua Yang, Yongfeng Cai, Qian Ma, Albert Xiong, P.T. Xu, Zhidan Zhang, Jiean Xu, Yaqi Zhou, Zhiping Liu, Dingwei Zhao, John M. Asara, Wei Li, Huidong Shi, Ruth B. Caldwell, Akrit Sodhi, Yuqing Huo · 发表于：Science Translational Medicine · 年份：2024 · DOI：10.1126/scitranslmed.adk3868 · 被引用次数：20 · 研究领域：Retinal Diseases and Treatments、Retinal Development and Disorders、Retinal Imaging and Analysis

Anti–vascular endothelial growth factor therapy has had a substantial impact on the treatment of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults. Despite treatment, many patients with nAMD still develop severe and irreversible visual impairment because of the development of subretinal fibrosis. We recently reported the anti-inflammatory and antiangiogenic effects of inhibiting the gene encoding adenosine receptor 2A ( Adora2a ), which has been implicated in cardiovascular disease. Here, using two mouse models of subretinal fibrosis (mice with laser injury–induced CNV or mice with a deficiency in the very low–density lipoprotein receptor), we found that deletion of Adora2a either globally or specifically in endothelial cells reduced subretinal fibrosis independently of angiogenesis. We showed that Adora2a -dependent endothelial-to-mesenchymal transition contributed to the development of subretinal fibrosis in mice with laser injury–induced CNV. Deficiency of Adora2a in cultured mouse and human choroidal endothelial cells suppressed induction of the endothelial-to-mesenchymal transition. A metabolomics analysis of cultured human choroidal endothelial cells showed that ADORA2A knockdown with an siRNA reversed the increase in succinate because of decreased succinate dehydrogenase B expression under fibrotic conditions. Pharmacological inhibition of ADORA2A with a small-molecu...