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Inactivation of adenosine receptor 2A suppresses endothelial-to-mesenchymal transition and inhibits subretinal fibrosis in mice.
- Source :
- Science Translational Medicine; 3/6/2024, Vol. 16 Issue 737, p1-15, 15p
- Publication Year :
- 2024
-
Abstract
- 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. Editor's summary: Retinal fibrosis reversal age-related macular degeneration (AMD) is driven by neovascularization and is associated with subretinal fibrosis. Working in mice with genetically induced AMD or with a laser-induced retinal injury, Yang et al. show that deleting the gene encoding adenosine receptor 2A (Adora2a) prevented subretinal fibrosis in both mouse models. Specifically, deleting Adora2a in endothelial cells was sufficient to reverse subretinal fibrosis by preventing endothelial-to-mesenchymal transition. In human choroidal endothelial cells, the authors showed that endothelial-to-mesenchymal transition was associated with succinate accumulation due to decreased succinate dehydrogenase subunit B expression. Treatment with an ADORA2A antagonist reversed subretinal fibrosis in both mouse models, suggesting that targeting ADORA2A in endothelial cells could be a therapeutic strategy to treat AMD. —Brandon Berry [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19466234
- Volume :
- 16
- Issue :
- 737
- Database :
- Complementary Index
- Journal :
- Science Translational Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 175875106
- Full Text :
- https://doi.org/10.1126/scitranslmed.adk3868