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-molecule KW6002 in both mouse models recapitulated the reduction in subretinal fibrosis observed in mice with genetic deletion of Adora2a . ADORA2A inhibition may be a therapeutic approach to treat subretinal fibrosis associated with nAMD.

中文翻译：

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腺苷受体 2A 失活可抑制小鼠内皮细胞向间质细胞的转变并抑制视网膜下纤维化

抗血管内皮生长因子治疗对新生血管性年龄相关性黄斑变性 (nAMD) 患者脉络膜新生血管 (CNV) 的治疗产生了重大影响，而新生血管性年龄相关性黄斑变性 (nAMD) 是老年人视力丧失的主要原因。尽管进行了治疗，许多 nAMD 患者由于视网膜下纤维化的发展，仍然出现严重且不可逆的视力障碍。我们最近报道了抑制编码腺苷受体 2A 的基因的抗炎和抗血管生成作用（阿多拉2a），这与心血管疾病有关。在这里，使用两种视网膜下纤维化小鼠模型（激光损伤诱导的 CNV 小鼠或极低密度脂蛋白受体缺陷的小鼠），我们发现缺失阿多拉2a整体或特异性地在内皮细胞中减少视网膜下纤维化，与血管生成无关。我们证明了阿多拉2a依赖于内皮到间质的转变导致了激光损伤诱导的 CNV 小鼠视网膜下纤维化的发生。缺乏阿多拉2a在培养的小鼠和人脉络膜内皮细胞中抑制内皮向间质转化的诱导。对培养的人脉络膜内皮细胞的代谢组学分析表明阿朵拉2A由于纤维化条件下琥珀酸脱氢酶 B 表达减少，用 siRNA 进行敲低可逆转琥珀酸的增加。在两种小鼠模型中用小分子 KW6002 对 ADORA2A 进行药理学抑制，重现了在基因缺失的小鼠中观察到的视网膜下纤维化的减少阿多拉2a。ADORA2A 抑制可能是治疗与 nAMD 相关的视网膜下纤维化的一种治疗方法。