Aims

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.

Materials and methods

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.

Key findings

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.

Significance

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.

中文翻译：

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体外 Akt 抑制可逆转去势诱导的阴部内动脉和阴茎内皮功能障碍

宗旨

雄激素剥夺疗法是一种常见的前列腺癌治疗方法，可使男性的睾酮水平降低。不幸的是，大多数缺乏睾酮的患者会遭受严重的勃起功能障碍 (ED) 并且没有有效的 ED 治疗选择。睾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功能。最近的证据表明睾酮激活雄激素受体 (AR) 并通过 Akt-内皮 NO 合酶 (eNOS) 途径产生一氧化氮 (NO)；然而，阉割如何影响这一信号通路仍然未知。

材料和方法

在这项研究中，我们使用手术阉割的大鼠模型来确定阉割如何通过 Akt-eNOS 通路影响离体阴部内动脉 (IPA) 和阴茎松弛。

主要发现

与全身血管系统不同，去势会导致显着的 IPA 和阴茎内皮功能障碍，并导致 AR 降低 50%。尽管睾酮和乙酰胆碱 (ACh) 都会使 Akt 和 eNOS 磷酸化，但阉割不会影响睾酮介导的 IPA 和阴茎 Akt 或 eNOS 磷酸化。令人惊讶的是，阉割增加了 ACh 介导的 Akt 和 eNOS 磷酸化，但降低了 eNOS 二聚体与单体的比例。使用 10DEBC 的 Akt 抑制保留了 IPA eNOS 二聚体。在功能上，10DEBC 可逆转去势诱导的离体 IPA 和阴茎内皮功能障碍。

意义

这些数据证明了阉割如何解偶联 eNOS，并提供了一种新的策略来改善勃起所必需的内皮依赖性松弛。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酮缺乏的前列腺癌幸存者的 ED。