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

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.