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Single\u2010cell RNA sequencing of human corpus cavernosum, \u00a0adenosine deaminase (ADA) and adenosine receptors knock\u2010out mice (ADA<jats:sup>\u2212\/\u2212<\/jats:sup>, A1<jats:sup>\u2212\/\u2212<\/jats:sup>, A2a<jats:sup>\u2212\/\u2212<\/jats:sup>, A2b<jats:sup>\u2212\/\u2212<\/jats:sup>, and A3<jats:sup>\u2212\/\u2212<\/jats:sup>), and primary corpus cavernosum smooth muscle cells\u00a0are used to determine receptor subtypes responsible for adenosine\u2010induced erection. Three rat models are established to characterize refractory erectile dysfunction (ED): age\u2010related ED, bilateral cavernous nerve crush related ED (BCNC), and diabetes mellitus\u2010induced ED. In single\u2010cell RNA sequencing data, the corpus cavernosum of ED patients show a decrease in adenosine A1, A2a and A2b receptors. In vivo, A2b receptor knock\u2010out abolishes adenosine\u2010induced erection but not that of A1, A2a, or A3 receptor. Under hypoxic conditions in vitro, activating the A2b receptor increases HIF\u20101\u03b1 and decreases PDE5 expression. In refractory ED models, activating the A2b receptor with Bay 60\u20136583 improves erectile function and down\u2010regulates HIF\u20101\u03b1 and TGF\u2010\u03b2. Administering Dipyridamole (40\u00a0mg\u00a0Kg<jats:sup>\u22121<\/jats:sup>) to BCNC rats improve penile adenosine levels and erectile function. Our study reveals that the A2b receptor mediates adenosine\u2010induced penile erection. Activating the A2b receptor promotes penile rehabilitation of refractory ED by alleviating hypoxia and fibrosis.<\/jats:p>","DOI":"10.1002\/advs.202306514","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T09:49:46Z","timestamp":1718358586000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Targeting Adenosine A2b Receptor Promotes Penile Rehabilitation of Refractory Erectile Dysfunction"],"prefix":"10.1002","volume":"11","author":[{"given":"Yang","family":"Xiong","sequence":"first","affiliation":[{"name":"Department of Urology and Andrology Laboratory West China Hospital Sichuan University  Chengdu Sichuan 610041 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology Laboratory West China Hospital Sichuan University  Chengdu Sichuan 610041 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