Skip to main content
Dryad

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

Abstract

The introduction of 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. Nonetheless, despite treatment, many patients with nAMD still develop severe and irreversible visual impairment due to the development of subretinal fibrosis. Therefore, therapeutic strategies that prevent or inhibit subretinal fibrosis are needed. We recently reported the anti-inflammatory and anti-angiogenic effects of inhibiting adenosine receptor 2A (ADORA2A), a gene previously implicated in cardiovascular diseases. Here we used laser injury-induced CNV and very low-density lipoprotein receptor-deficient mice as models of subretinal fibrosis and found that subretinal fibrosis was reduced in these mice in the absence of Adora2a globally or endothelial-specifically. This decreased fibrosis was independent of angiogenesis. Mechanistically, endothelial-to-mesenchymal transition (EndMT) played a major role in the development of subretinal fibrosis in these models. Deficiency of Adora2a in choroidal endothelial cells (CECs) suppressed induction of EndMT and resulted in decreased subretinal fibrosis. The metabolomic profile of cultured CECs showed decreased succinate under ADORA2A deficiency, a product associated with succinate dehydrogenase (SDH) of the tricarboxylic acid pathway, suggesting a role for the ADORA2A-SDH-succinate axis in subretinal fibrosis. Pharmacologic inhibition of ADORA2A with KW6002 recapitulated the subretinal fibrotic phenotypes previously observed in mice with genetic Adora2a deficiency. Therefore, this study indicated that ADORA2A inhibition may be an approach to prevent or treat subretinal fibrosis associated with nAMD.