Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA; Department of Surgery, Division of Urology, Duke University Medical Center, Durham, NC, USA.
Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
Life Sci. 2021 Nov 15;285:119966. doi: 10.1016/j.lfs.2021.119966. Epub 2021 Sep 17.
Androgen deprivation therapy is a common prostate cancer treatment which causes men to have castrate levels of testosterone. Unfortunately, most testosterone deficient patients will suffer severe erectile dysfunction (ED) and have no effective ED treatment options. Testosterone deficiency causes endothelial dysfunction and impairs penile vasodilation necessary to maintain an erection. Recent evidence demonstrates testosterone activates androgen receptors (AR) and generates nitric oxide (NO) through the Akt-endothelial NO synthase (eNOS) pathway; however, it remains unknown how castration impacts this signaling pathway.
In this study, we used a surgically castrated rat model to determine how castration impacts ex vivo internal pudendal artery (IPA) and penile relaxation through the Akt-eNOS pathway.
Unlike systemic vasculature, castration causes significant IPA and penis endothelial dysfunction associated with a 50% AR reduction. Though testosterone and acetylcholine (ACh) both phosphorylate Akt and eNOS, castration did not affect testosterone-mediated IPA and penile Akt or eNOS phosphorylation. Surprisingly, castration increases ACh-mediated Akt and eNOS phosphorylation but reduces the eNOS dimer to monomer ratio. Akt inhibition using 10DEBC preserves IPA eNOS dimers. Functionally, 10DEBC reverses castration induced ex vivo IPA and penile endothelial dysfunction.
These data demonstrate how castration uncouples eNOS and provide a novel strategy for improving endothelial-dependent relaxation necessary for an erection. Further studies are needed to determine if Akt inhibition may treat or even prevent ED in testosterone deficient prostate cancer survivors.
去势治疗是一种常见的前列腺癌治疗方法，会导致男性的睾丸酮水平降至去势水平。不幸的是，大多数睾丸酮缺乏的患者会出现严重的勃起功能障碍（ED），并且没有有效的 ED 治疗选择。睾丸酮缺乏会导致内皮功能障碍，并损害维持勃起所必需的阴茎血管舒张。最近的证据表明，睾丸酮通过 Akt-内皮型一氧化氮合酶（eNOS）途径激活雄激素受体（AR）并产生一氧化氮（NO）；然而，去势如何影响这条信号通路仍不清楚。
在这项研究中，我们使用手术去势的大鼠模型来确定去势如何通过 Akt-eNOS 途径影响离体阴部内动脉（IPA）和阴茎松弛。
与全身血管系统不同，去势会导致 IPA 和阴茎内皮功能障碍显著，与 AR 减少 50%相关。尽管睾丸酮和乙酰胆碱（ACh）都能使 Akt 和 eNOS 磷酸化，但去势并不影响睾丸酮介导的 IPA 和阴茎 Akt 或 eNOS 磷酸化。令人惊讶的是，去势增加了 ACh 介导的 Akt 和 eNOS 磷酸化，但降低了 eNOS 二聚体到单体的比值。使用 10DEBC 抑制 Akt 可保留 IPA eNOS 二聚体。在功能上，10DEBC 逆转了去势引起的离体 IPA 和阴茎内皮功能障碍。
这些数据表明去势如何使 eNOS 解偶联，并为改善勃起所必需的内皮依赖性松弛提供了一种新的策略。需要进一步的研究来确定 Akt 抑制是否可以治疗甚至预防睾丸酮缺乏的前列腺癌幸存者的 ED。
