The role of mechano-regulated YAP/TAZ in erectile dysfunction
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39009-z |
| _version_ | 1797795562999775232 |
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| author | 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 Lei Chang |
| author_facet | 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 Lei Chang |
| author_sort | Mintao Ji |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T03:19:51Z |
| format | Article |
| id | doaj.art-1f289ecf120a4ab8a7bbff763f282810 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T03:19:51Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-1f289ecf120a4ab8a7bbff763f2828102023-06-25T11:22:11ZengNature PortfolioNature Communications2041-17232023-06-0114111610.1038/s41467-023-39009-zThe role of mechano-regulated YAP/TAZ in erectile dysfunctionMintao Ji0Dongsheng Chen1Yinyin Shu2Shuai Dong3Zhisen Zhang4Haimeng Zheng5Xiaoni Jin6Lijun Zheng7Yang Liu8Yifei Zheng9Wensheng Zhang10Shiyou Wang11Guangming Zhou12Bingyan Li13Baohua Ji14Yong Yang15Yongde Xu16Lei Chang17State 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 UniversityInstitute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, and Suzhou Institute of Systems MedicineState 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityState 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 UniversityDepartment of Urology, The Affiliated Hospital of Changchun University of Chinese MedicineInstitute of Biomechanics and Applications, Department of Engineering Mechanics, Zhejiang UniversityBinzhou Medical UniversityInstitute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, and Suzhou Institute of Systems MedicineState 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 UniversityDepartment of Nutrition and Food Hygiene, Soochow University of Public HealthInstitute of Biomechanics and Applications, Department of Engineering Mechanics, Zhejiang UniversityDepartment of Urology, The Affiliated Hospital of Changchun University of Chinese MedicineDepartment of Urology, Beijing Friendship Hospital, Capital Medical UniversityState 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 UniversityAbstract 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.https://doi.org/10.1038/s41467-023-39009-z |
| spellingShingle | 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 Lei Chang The role of mechano-regulated YAP/TAZ in erectile dysfunction Nature Communications |
| title | The role of mechano-regulated YAP/TAZ in erectile dysfunction |
| title_full | The role of mechano-regulated YAP/TAZ in erectile dysfunction |
| title_fullStr | The role of mechano-regulated YAP/TAZ in erectile dysfunction |
| title_full_unstemmed | The role of mechano-regulated YAP/TAZ in erectile dysfunction |
| title_short | The role of mechano-regulated YAP/TAZ in erectile dysfunction |
| title_sort | role of mechano regulated yap taz in erectile dysfunction |
| url | https://doi.org/10.1038/s41467-023-39009-z |
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