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While current ROP treatments are mostly disruptive to reduce proliferative neovascularization by targeting the hypoxic phase, protection against early hyperoxia\u2010induced retinal vascular loss represents an effective therapeutic window, but no such therapeutic strategy is available. Built upon our recent demonstration that the protection against oxygen\u2010induced retinopathy by adenosine A\n                    <jats:sub>2A<\/jats:sub>\n                    receptor (A\n                    <jats:sub>2A<\/jats:sub>\n                    R) antagonists is most effective when administered at the hyperoxia (not hypoxic) phase, we here uncovered the cellular mechanism underlying the A\n                    <jats:sub>2A<\/jats:sub>\n                    R\u2010mediated protection against early hyperoxia\u2010induced retinal vascular loss by reversing the inhibition of cellular proliferation via possibly multiple signaling pathways. Specifically, we revealed two distinct stages of the hyperoxia phase with greater cellular proliferation and apoptosis activities and upregulation of adenosine signaling at postnatal 9\u00a0day (P9) but reduced cellular activities and adenosine\u2010A\n                    <jats:sub>2A<\/jats:sub>\n                    R signaling at P12. Importantly, the A\n                    <jats:sub>2A<\/jats:sub>\n                    R\u2010mediated protection at P9 was associated with the reversal of hyperoxia\u2010induced inhibition of progenitor cells at the peripheral retina at P9 and of retinal endothelial proliferation at P9 and P12. The critical role of cellular proliferation in the hyperoxia\u2010induced retinal vascular loss was validated by the increased avascular areas by siRNA knockdown of the multiple signaling molecules involved in modulation of cellular proliferation, including activin receptor\u2010like kinase 1, DNA\u2010binding protein inhibitor 1, and vascular endothelial growth factor\u2010A.\n                  <\/jats:p>","DOI":"10.1096\/fj.202100414rr","type":"journal-article","created":{"date-parts":[[2021,8,21]],"date-time":"2021-08-21T16:15:46Z","timestamp":1629562546000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Adenosine A\n                    <sub>2A<\/sub>\n                    receptor antagonism protects against hyperoxia\u2010induced retinal vascular loss via cellular 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Optometry, Ophthalmology and Vision Science The Affiliated Eye Hospital Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Optometry, Ophthalmology and Vision Science The Affiliated Eye Hospital Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Optometry, Ophthalmology and Vision Science The Affiliated Eye Hospital Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Optometry, Ophthalmology and Vision Science The Affiliated Eye Hospital Wenzhou Medical University Wenzhou 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