Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism
Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism
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DOI：
10.1073/pnas.0407183102
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发表时间：
2005-02-01
影响因子：
11.1
通讯作者：
Burnett, AL
中科院分区：
文献类型：
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作者：
Champion, HC;Bivalacqua, TJ;Burnett, AL
阴茎异常勃起的分子机制尚未明确。虽然已知在正常情况下一氧化氮（NO）途径介导阴茎勃起，但基于我们之前的发现，即缺乏内皮型一氧化氮合酶基因的小鼠（eNOS（-/-））以及缺乏神经元型一氧化氮合酶（nNOS）和内皮型一氧化氮合酶（nNOS（-/-），eNOS（-/-））的小鼠有阴茎异常勃起活动的倾向，我们假设阴茎异常勃起的机制在于该途径的异常下游信号传导。我们研究了下游鸟苷酸环化酶和5型磷酸二酯酶（PDE5A）的表达及功能在eNOS（-/-）和nNOS（-/-），eNOS（-/-）小鼠中对这些反应的介导作用。在eNOS（-/-）和nNOS（-/-），eNOS（-/-）小鼠中，对海绵体神经刺激以及海绵体内注射一氧化氮供体二乙胺 - 一氧化氮复合物的勃起反应增强，但在野生型（WT）或nNOS（-/-）小鼠中未增强。在eNOS（-/-）和nNOS（-/-），eNOS（-/-）小鼠中，PDE5A蛋白表达、活性以及环鸟苷酸（cGMP）水平显著降低，并且这种效应在暴露于一氧化氮合酶抑制剂的野生型海绵体中重现。此外，海绵体神经刺激与海绵体cGMP水平的显著升高相关，这表明尽管在基线水平较低，但在神经刺激时，eNOS（-/-）和nNOS（-/-），eNOS（-/-）小鼠中cGMP的产生不受控制。用编码eNOS的腺病毒转染eNOS（-/-）小鼠导致PDE5A蛋白和活性正常化以及阴茎异常勃起活动得到纠正。再加上镰状细胞病小鼠（表现出阴茎异常勃起表型）显示出PDE5A表达/活性失调的观察结果，这些数据表明PDE5A失调是阴茎异常勃起的一个基本机制。
The molecular mechanism for priapism is not well characterized. Although the nitric oxide (NO) pathway is known to mediate penile erection under normal conditions, we hypothesized that the mechanism of priapism rests in aberrant downstream signaling of this pathway based on our previous findings that mice lacking the gene for endothelial nitric oxide synthase (eNOS(-/-)) and mice lacking both neuronal NOS (nNOS) and eNOS (nNOS(-/-), eNOS(-/-)) have a tendency for priapic activity. We investigated the role of downstream guanylate cyclase and phosphodiesterase type 5 (PDE5A) expression and function in mediating these responses in eNOS(-/-) and nNOS(-/-), eNOS(-/-) mice. Erectile responses to both cavernous nerve stimulation and intracavernosal injection of the NO donor diethylamine-NONOate were augmented in eNOS(-/-) and nNOS(-/-), eNOS(-/-) mice but not in WT or nNOS(-/-) mice. PDE5A protein expression and activity and cGMP levels were significantly lower in eNOS(-/-) and nNOS(-/-), eNOS(-/-) mice, and this effect was reproduced in WT corpus cavernosum exposed to NOS inhibitors. Moreover, cavernous nerve stimulation was associated with a marked augmentation of cavernosal cGMP levels, suggesting that, although lower at baseline, the production of cGMP is unchecked in eNOS(-/-) and nNOS(-/-), eNOS(-/-) mice upon neurostimulation. Transfection of eNOS(-/-) mice with an adenovirus encoding eNOS resulted in a normalization of PDE5A protein and activity as well as a correction of priapic activity. Coupled with the observation that sickle cell disease mice (which show a priapism phenotype) evince dysregulated PDE5A expression/activity, these data suggest that PDE5A dysregulation is a fundamental mechanism for priapism.