TEAD1介导的阴茎海绵体平滑肌细胞表型转化在糖尿病性ED中的作用及机制研究

Phenotypic modulation of corpus cavernosum smooth muscle cells (CCSMCs)plays a key role in the pathogenesis of diabetic rats with erectile dysfunction (ED), but its exactly mechanism is still unclear. Recent studies have found that transcriptional factor TEAD1 can regulate vascular smooth muscle cells (VSMCs) phenotypic modulation by interfere with myocardin. However, whether TEAD1 can affect diabetic rats’erectile function by regulating phenotypic modulation of CCSMCs of diabetic rats interfere with myocardin are unknown, and the relationship between them also are very unclear. We have confirmed that myocardin can improve rats’erectile function by reversing the phenotype of diabetic rat CCSMCs, and we also found that knockdown of can TEAD1 induced myocardin protein and mRNA expression in addition to increasing expression of smooth muscle-specific. Therefore,we hypothesize that TEAD1 is critical for promoting phenotypic modulation in diabeteic rat CCSMCs, and it can improve the erectile function by interfering with myocardin. Our experimental results will further perfect the theory of signaling pathway in the process of regulating penis erectile and provide experimental data for a new molecular target.

阴茎海绵体平滑肌细胞（CCSMCs）表型转化是导致糖尿病性大鼠勃起功能障碍（ED）的重要病理基础，但其机制仍不清楚。研究证实TEAD1通过干扰myocardin的活性使血管平滑肌细胞发生表型转化，但它们是否能调控糖尿病性大鼠CCSMCs表型，进而影响其勃起功能，以及它们之间的信号通路网络关系不清楚。已有研究证实在阴茎海绵体组织中过表达myocardin基因可以逆转糖尿病性ED大鼠CCSMCs表型进而改善其勃起功能，另外，我们近期研究发现TEAD1敲减后的糖尿病性ED大鼠CCSMCs中myocardin表达明显上调，同时平滑肌特异性收缩型标记物的表达也明显升高。故我们推测TEAD1可能通过影响myocardin的功能而促进糖尿病性大鼠CCSMCs发生表型转化，进而使其发生ED。研究结果将有助于完善阴茎勃起调控过程中的信号通路理论，最终为明确糖尿病性ED发病机制及新分子靶标的确立提供实验依据。

男性勃起功能障碍（ED）是男科常见病，且严重被低估的泌尿男科疾病。流行病学调查研究报道糖尿病与ED的发生密切相关，35-90%的糖尿病患者伴有ED。阴茎海绵体平滑肌细胞（CCSMCs）表型转化是导致糖尿病性ED的重要病理基础，但其机制仍不清楚。研究证实TEAD1通过干扰myocardin的活性使血管平滑肌细胞发生表型转化，但它们是否能调控糖尿病性大鼠CCSMCs表型，进而影响其勃起功能，以及它们之间的信号通路网络关系不清楚。已有研究表明在阴茎海绵体组织中过表达myocardin基因可以逆转糖尿病性ED大鼠CCSMCs表型进而改善其勃起功能。因此，本项目通过细胞实验、动物实验，使用载体构建、病毒包装、基因转染、qRT-PCR、western blot等分子生物学技术多方面深入研究TEAD1介导的阴茎海绵体平滑肌细胞表型转化在糖尿病性ED中的作用及机制。结果发现，TEAD1在糖尿病性ED大鼠阴茎组织及CCSMCs中的高表达明显增强，TEAD1敲减后的糖尿病性ED大鼠CCSMCs中myocardin表达明显上调，同时平滑肌特异性收缩型标记物的表达也明显升高，敲除TEAD1基因可改善糖尿病性ED大鼠阴茎勃起功能，同时发现敲除TEAD1基因的大鼠阴茎组织myocardin表达显著升高，且CCSMCs表型由增殖表型向合成型转化。故我们认为TEAD1通过抑制myocardin的表达而促进糖尿病性大鼠CCSMCs发生表型转化，进而使其发生ED。研究结果将有助于完善阴茎勃起调控过程中的信号通路理论，最终为明确糖尿病性ED发病机制及新分子靶标的确立提供实验依据。