State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Medical College of Soochow University, 215123, Suzhou, China.
Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, and Suzhou Institute of Systems Medicine, 215123, Suzhou, China.
Nat Commun. 2023 Jun 23;14(1):3758. doi: 10.1038/s41467-023-39009-z.
Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of patients, approximately 30%, do not respond to PDE5i treatment. Therefore, new treatment methods are needed. In this study, we identified a pathway that contributes to male erectile function. We show that mechano-regulated YAP/TAZ signaling in smooth muscle cells (SMCs) upregulates adrenomedullin transcription, which relaxed the SMCs to maintain erection. Using single-nucleus RNA sequencing, we investigated how penile erection stretches the SMCs, inducing YAP/TAZ activity. Subsequently, we demonstrate that YAP/TAZ plays a role in erectile function and penile rehabilitation, using genetic lesions and various animal models. This mechanism relies on direct transcriptional regulation of adrenomedullin by YAP/TAZ, which in turn modulates penile smooth muscle contraction. Importantly, conventional PDE5i, which targets NO-cGMP signaling, does not promote erectile function in YAP/TAZ-deficient ED model mice. In contrast, by activating the YAP/TAZ-adrenomedullin cascade, mechanostimulation improves erectile function in PDE5i nonrespondent ED model rats and mice. Furthermore, using clinical retrospective observational data, we found that mechanostimulation significantly promotes erectile function in patients irrespective of PDE5i use. Our studies lay the groundwork for exploring the mechano-YAP/TAZ-adrenomedullin axis as a potential target in the treatment of ED.
磷酸二酯酶 5 型抑制剂（PDE5is）是治疗勃起功能障碍（ED）的主要治疗选择。然而，相当一部分患者（约 30%）对 PDE5i 治疗无反应。因此，需要新的治疗方法。在这项研究中，我们确定了一条促进男性勃起功能的途径。我们表明，平滑肌细胞（SMCs）中的机械调节 YAP/TAZ 信号上调肾上腺髓质素转录，从而使 SMC 松弛以维持勃起。通过单细胞 RNA 测序，我们研究了阴茎勃起如何拉伸 SMC，从而诱导 YAP/TAZ 活性。随后，我们使用基因损伤和各种动物模型证明了 YAP/TAZ 在勃起功能和阴茎康复中的作用。这种机制依赖于 YAP/TAZ 对肾上腺髓质素的直接转录调节，进而调节阴茎平滑肌收缩。重要的是，针对 NO-cGMP 信号的传统 PDE5i 在 YAP/TAZ 缺陷型 ED 模型小鼠中不能促进勃起功能。相比之下，机械刺激通过激活 YAP/TAZ-肾上腺髓质素级联反应，改善了 PDE5i 无反应的 ED 模型大鼠和小鼠的勃起功能。此外，使用临床回顾性观察数据，我们发现机械刺激无论 PDE5i 使用情况如何，都能显著促进患者的勃起功能。我们的研究为探索机械 YAP/TAZ-肾上腺髓质素轴作为 ED 治疗的潜在靶点奠定了基础。
