The Role of Mechanoregulated YAP/TAZ in Erectile Dysfunction

Phosphodiesterase type 5 inhibitors (PDE5is) are the primary therapeutic option for erectile dysfunction. However, 30% of patients do not respond to PDE5is treatment, making the quest for a new treatment modality a central endeavor. Here, we found a new pathway in erectile function control, mechano-regulated YAP/TAZ activate Adrenomedullin transcription, which sustains smooth muscle cells (SMCs) relaxation to maintain the erection. We first found that penile erection stretches the SMCs, dominating YAP/TAZ activity. Subsequently, we showed that YAP/TAZ plays a vital role in erectile function and penile rehabilitation using genetic lesions and several animal models. The mechanism relies on the regulation of Adrenomedullin on penile SMCs contraction, which we identify here as a direct YAP/TAZ transcript. Notably, conventional PDE5is targeting NO-cGMP signaling do not cure YAP/TAZ deficient ED. In contrast, by activating YAP/TAZ-Adrenomedullin cascade, mechano-stimulation improved erectile function, including PDE5is non-responders in both experimental models and clinical trials. Our studies lay the groundwork for exploring mechano-YAP/TAZ-Adrenomedullin as prospective targets in the treatment of ED5型磷酸二酯酶抑制剂（Phosphodiesterase type 5 inhibitors, PDE5is）是治疗勃起功能障碍（Erectile Dysfunction, ED）的一线治疗手段。然而，有30%的患者对PDE5is治疗无应答，这使得开发新型治疗方式成为该领域的核心任务。本研究首次发现了一条调控勃起功能的新通路：机械力调控的YAP/TAZ可激活肾上腺髓质素（Adrenomedullin）的转录，进而维持平滑肌细胞（Smooth Muscle Cells, SMCs）的舒张状态以保障勃起功能。我们首先证实，阴茎勃起过程会牵拉平滑肌细胞，这是调控YAP/TAZ活性的主导因素。随后，通过基因缺陷模型与多种动物实验模型，我们证明了YAP/TAZ在勃起功能与阴茎康复中发挥关键作用。该机制依赖于肾上腺髓质素对阴茎平滑肌细胞收缩的调控，我们在此证实该基因为YAP/TAZ的直接转录靶标。值得注意的是，传统靶向NO-cGMP信号通路的PDE5is无法治愈YAP/TAZ缺陷型勃起功能障碍。与之相反，通过激活YAP/TAZ-肾上腺髓质素信号级联反应，机械刺激可改善勃起功能，这一效果在实验模型与临床试验中均覆盖了PDE5is无应答患者。本研究为将机械-YAP/TAZ-肾上腺髓质素通路作为勃起功能障碍治疗的潜在靶点奠定了理论基础。