Phosphorylated endothelial nitric oxide synthase mediates vascular endothelial growth factor-induced penile erection
Phosphorylated endothelial nitric oxide synthase mediates vascular endothelial growth factor-induced penile erection
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DOI：
10.1095/biolreprod.103.021113
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发表时间：
2004-02-01
影响因子：
3.6
通讯作者：
Burnett, AL
中科院分区：
文献类型：
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作者：
Musicki, B;Palese, MA;Burnett, AL
本研究的目的是评估血管内皮生长因子（VEGF）诱导的阴茎勃起是否是通过磷酸化内皮一氧化氮合酶（eNOS）的激活介导的。我们使用有或没有血管性勃起功能障碍的野生型 (WT) 和 eNOS 敲除 (eNOS(-/-)) 小鼠评估了组成型激活的 eNOS 在 VEGF 诱导的阴茎勃起中的作用。对成年WT和eNOS(-/-)小鼠进行假手术或双侧去势以诱导血管源性勃起功能障碍。手术时，向动物海绵体内注射表达人 VEGF145 的复制缺陷型腺病毒（109 个颗粒单位）或空病毒（Ad.Null）。 7天后，评估对海绵神经电刺激的勃起功能。使用蛋白质免疫印迹和免疫组织化学对小鼠阴茎中的总蛋白激酶 B (Akt) 和磷酸化蛋白激酶 B (Akt) 以及总 eNOS 和磷酸化进行定量评估。在完整的WT小鼠中，VEGF145显着增加了勃起反应，而在去势后的WT小鼠中，它完全恢复了阴茎勃起。然而，VEGF145 未能增加完整 eNOS(-/-) 小鼠的勃起反应，并且仅部分恢复去势 eNOS(-/-) 小鼠的勃起功能。此外，在完整和去势WT小鼠的阴茎中，VEGF145显着增加了丝氨酸1177处的eNOS磷酸化约2倍。这些数据为 VEGF 对阴茎勃起的刺激作用提供了分子解释，其中涉及磷酸化 eNOS（丝氨酸 1177）的介导。
The objective of the present study was to evaluate whether vascular endothelial growth factor (VEGF)-induced penile erection is mediated by activation of endothelial nitric oxide synthase (eNOS) through its phosphorylation. We assessed the role of constitutively activated eNOS in VEGF-induced penile erection using wild-type (WT) and eNOS-knockout (eNOS(-/-)) mice with and without vasculogenic erectile dysfunction. Adult WT and eNOS(-/-) mice were subjected to sham operation or bilateral castration to induce vasculogenic erectile dysfunction. At the time of surgery, animals were injected intracavernosally with a replication-deficient adenovirus expressing human VEGF145 (109 particle units) or with empty virus (Ad.Null). After 7 days, erectile function was assessed in response to cavernous nerve electrical stimulation. Total and phosphorylated protein kinase B (Akt) as well as total and phosphorylated eNOS were quantitatively assessed in mice penes using Western immunoblot and immunohistochemistry. In intact WT mice, VEGF145 significantly increased erectile responses, and in WT mice after castration, it completely recovered penile erection. However, VEGF145 failed to increase erectile responses in intact eNOS(-/-) mice and only partially recovered erectile function in castrated eNOS(-/-) mice. In addition, VEGF145 significantly increased phosphorylation of eNOS at Serine 1177 by approximately 2-fold in penes of both intact and castrated WT mice. The data provide a molecular explanation for VEGF stimulatory effect on penile erection, which involves phosphorylated eNOS (Serine 1177) mediation.