Department of Urology and Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Division of Urology, University of Texas Medical School at Houston, Houston, TX, 77030, USA.
Adv Sci (Weinh). 2024 Aug;11(30):e2306514. doi: 10.1002/advs.202306514. Epub 2024 Jun 14.
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) 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.
腺苷及特定腺苷受体亚型促进阴茎康复的机制尚不清楚。通过对人海绵体的单细胞 RNA 测序、腺苷脱氨酶（ADA）和腺苷受体敲除小鼠（ADA、A1、A2a、A2b 和 A3）以及原代海绵体平滑肌细胞，确定负责腺苷诱导勃起的受体亚型。建立了三种大鼠模型来描述难治性勃起功能障碍（ED）：与年龄相关的 ED、双侧海绵体神经挤压相关的 ED（BCNC）和糖尿病诱导的 ED。在单细胞 RNA 测序数据中，ED 患者的海绵体中腺苷 A1、A2a 和 A2b 受体减少。在体内，A2b 受体敲除消除了腺苷诱导的勃起，但不消除 A1、A2a 或 A3 受体的勃起。在体外缺氧条件下，激活 A2b 受体增加 HIF-1α并降低 PDE5 的表达。在难治性 ED 模型中，用 Bay 60-6583 激活 A2b 受体可改善勃起功能并下调 HIF-1α和 TGF-β。给 BCNC 大鼠给予双嘧达莫（40mg/kg）可提高阴茎内腺苷水平并改善勃起功能。我们的研究表明，A2b 受体介导了腺苷诱导的阴茎勃起。激活 A2b 受体通过减轻缺氧和纤维化来促进难治性 ED 的阴茎康复。
