Update on corpus cavernosum smooth muscle contractile pathways in erectile function: a role for testosterone?
Update on corpus cavernosum smooth muscle contractile pathways in erectile function: a role for testosterone?
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DOI：
10.1111/j.1743-6109.2011.02218.x
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发表时间：
2011-07
期刊：
影响因子：
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通讯作者：
Xinhua Zhang;A. Melman;M. DiSanto
中科院分区：
文献类型：
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作者：
Xinhua Zhang;A. Melman;M. DiSanto
简介 正常的勃起功能 (EF) 涉及供应阴茎和海绵体平滑肌 (CCSM) 的动脉的协调松弛，导致血窦扩张和海绵体内压力增加。但 CCSM 大部分时间都处于收缩状态，这是由神经末梢释放的去甲肾上腺素和内皮细胞释放的内皮素等其他血管收缩剂介导的。这些药物通过升高细胞内钙而引起平滑肌肌球蛋白 (SMM) 磷酸化。当钙恢复到基础水平时，钙敏感性增加并阻止肌球蛋白去磷酸化，这涉及 RhoA/Rho 激酶 (ROK) 机制，从而维持力量。尽管越来越多的证据表明雄激素对 EF 具有重大影响，而不仅仅是中枢介导的，但这一观点仍然颇具争议。目的 总结目前关于 CCSM 收缩通路的知识、它们在调节 EF 中的作用以及雄激素的影响。方法本文回顾了文献，并包含一些先前未发表的有关 CCSM 收缩信号传导的数据，包括已知雄激素在调节这些途径中发挥的作用。主要成果衡量指标 数据来自同行评审出版物和之前未发表的观察结果。结果 除了下调许多促勃起分子机制外，睾酮 (T) 水平降低还会上调 CCSM 收缩性，包括对 α-肾上腺素能激动剂的高反应性、SMM 磷酸化增加、SMM 亚型组成改变、RhoA/ROK 信号传导激活以及 CCSM 张力的 1-磷酸鞘氨醇调节。结论 T 水平降低会上调 CCSM 收缩信号。同时，它下调 CCSM 松弛通路，协同产生勃起功能障碍 (ED)。尽管一些泌尿科医生和研究人员仍然对雄激素对阴茎勃起的影响持怀疑态度，但了解这些分子控制机制以及雄激素对这些途径的影响应该为支持雄激素在 EF 中的作用提供新的证据，并促进治疗 ED 药物开发新靶点的发现。
INTRODUCTION Normal erectile function (EF) involves a coordinated relaxation of the arteries that supply the penis and the corpus cavernosum smooth muscle (CCSM), resulting in expansion of the sinusoids and increased intracavernous pressure. But the CCSM spends the majority of its time in the contracted state which is mediated by norepinephrine released from nerve endings and other vasoconstrictors like endothelins released from the endothelium. These agents cause smooth muscle myosin (SMM) phosphorylation by elevating intracellular calcium. When calcium returns to basal levels, the calcium sensitivity increases and prevents myosin dephosphorylation, which involves the RhoA/Rho-kinase (ROK) mechanism, thus maintaining force. Although mounting evidences demonstrate that androgens have a major influence on EF that is not just centrally mediated, this notion remains quite controversial. AIM To summarize the current knowledge on CCSM contractile pathways, the role they play in modulating EF, and the influence of androgens. METHODS The article reviews the literature and contains some previously unpublished data on CCSM contraction signaling including the role that androgens are known to play in modulating these pathways. MAIN OUTCOME MEASURES Data from peer-reviewed publications and previously unpublished observations. RESULTS In addition to downregulation of many pro-erectile molecular mechanisms, decreased testosterone (T) levels upregulate CCSM contractility, including hyperresponsiveness to α-adrenergic agonists, increased SMM phosphorylation, alteration of SMM isoform composition, activation of RhoA/ROK signaling and modulation of sphingosine-1-phosphate regulation of CCSM tone. CONCLUSIONS Decreased T levels upregulate CCSM contractile signaling. Meanwhile, it downregulates CCSM relaxation pathways synergizing to produce erectile dysfunction (ED). Although some urologists and researchers are still skeptical of the influence of androgens on penile erection, understanding these molecular control mechanisms as well as the influence that androgens have on these pathways should provide new evidence supporting the roles of androgens in EF and enhance the discovery of novel targets for drug development to treat ED.