Targeting Adenosine A2b Receptor Promotes Penile Rehabilitation of Refractory Erectile Dysfunction

The mechanisms of adenosine and specific Adenosine Receptor subtypes in promoting penile rehabilitation remain unclear. Single-cell RNA Sequencing of human corpus cavernosum, Adenosine Deaminase (ADA) and adenosine receptors knock-out mice (ADA^-/-, A1^-/-, A2a^-/-, A2b^-/-, and A3^-/-), and primary corpus cavernosum smooth muscle cells are used to determine receptor subtypes responsible for adenosine-induced erection. Three rat models are established to characterize refractory erectile dysfunction (ED): age-related ED, bilateral cavernous nerve crush related ED (BCNC), and diabetes mellitus-induced ED. In single-cell RNA Sequencing data, the corpus cavernosum of ED patients show a decrease in adenosine A1, A2a and A2b receptors. In vivo, A2b receptor knock-out abolishes adenosine-induced erection but not that of A1, A2a, or A3 receptor. Under hypoxic conditions in vitro, activating the A2b receptor increases HIF-1α and decreases PDE5 expression. In refractory ED models, activating the A2b receptor with Bay 60-6583 improves erectile function and down-regulates HIF-1α and TGF-β. Administering Dipyridamole (40 mg Kg^-1) to BCNC rats improve penile adenosine levels and erectile function. Our study reveals that the A2b receptor mediates adenosine-induced penile erection. Activating the A2b receptor promotes penile rehabilitation of refractory ED by alleviating hypoxia and fibrosis.