The role of mechano-regulated YAP/TAZ in erectile dysfunction

Mintao Ji, Dongsheng Chen, Yinyin Shu, Shuai Dong, Zhisen Zhang, Haimeng Zheng, Xiaoni Jin, Lijun Zheng, Yang Liu, Yifei Zheng, Wensheng Zhang, Shiyou Wang, Guangming Zhou, Bingyan Li, Baohua Ji, Yong Yang (), Yongde Xu () and Lei Chang ()
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Mintao Ji: Medical College of Soochow University
Dongsheng Chen: Chinese Academy of Medical Sciences & Peking Union Medical College, and Suzhou Institute of Systems Medicine
Yinyin Shu: Medical College of Soochow University
Shuai Dong: Medical College of Soochow University
Zhisen Zhang: Medical College of Soochow University
Haimeng Zheng: Medical College of Soochow University
Xiaoni Jin: Medical College of Soochow University
Lijun Zheng: Medical College of Soochow University
Yang Liu: The Affiliated Hospital of Changchun University of Chinese Medicine
Yifei Zheng: Zhejiang University
Wensheng Zhang: Binzhou Medical University
Shiyou Wang: Chinese Academy of Medical Sciences & Peking Union Medical College, and Suzhou Institute of Systems Medicine
Guangming Zhou: Medical College of Soochow University
Bingyan Li: Soochow University of Public Health
Baohua Ji: Zhejiang University
Yong Yang: The Affiliated Hospital of Changchun University of Chinese Medicine
Yongde Xu: Beijing Friendship Hospital, Capital Medical University
Lei Chang: Medical College of Soochow University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39009-z

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