National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea.
J Sex Med. 2014 Jan;11(1):51-63. doi: 10.1111/jsm.12329. Epub 2013 Sep 25.
Men with erectile dysfunction (ED) respond poorly to oral phosphodiesterase-5 inhibitors following radical prostatectomy. Recent studies have reported that up-regulation of transforming growth factor-β1 (TGF-β1) and activation of the Smad signaling pathway play important roles in cavernous fibrosis and in the deterioration of erectile function in a mouse model of cavernous nerve injury (CNI) and in patients with spinal cord injury. The mothers against decapentaplegic homolog 7 (Smad7) is known to inhibit the phosphorylation of Smad2 and Smad3.
To investigate the effectiveness of adenoviruses encoding Smad7 gene (Ad-Smad7) on erectile function in a mouse model of CNI.
Twelve-week-old C57BL/6J mice were used and distributed into 7 groups: sham operation group, untreated CNI group, and CNI groups receiving a single intracavernous injection of adenovirus encoding LacZ (1 × 10(8) virus particles [vp]/20 μL) or adenovirus encoding Smad7 (Ad-Smad7; 1 × 10(7), 1 × 10(8), 2 × 10(8), or 1 × 10(9) vp/20 μL).
Two weeks after bilateral cavernous nerve crushing and treatment, erectile function was measured by electrical stimulation of the cavernous nerve. The penis was harvested for histologic examinations and Western blot analysis.
The highest erectile response was noted in CNI mice treated with Ad-Smad7 at a dose of 1 × 10(8) vp, which reached up to 82-85% of sham control values. Local delivery of Ad-Smad7 significantly decreased endothelial cell apoptosis and the production of extracellular matrix proteins, including plasminogen activator inhibitor-1, fibronectin, collagen I, and collagen IV, and induced endothelial nitric oxide synthase phosphorylation in the corpus cavernosum tissue of CNI mice.
The adenovirus-mediated gene transfer of Smad7 successfully restored erectile function by enhancing endothelial cell function and through antifibrotic effects. These findings suggest that inhibition of the TGF-β signaling pathway by use of Smad7 may represent a promising therapeutic strategy for ED induced by radical prostatectomy.
行根治性前列腺切除术的男性患者在服用磷酸二酯酶-5 抑制剂后，其勃起功能障碍（ED）的治疗效果往往不佳。最近的研究表明，在海绵体神经损伤（CNI）的小鼠模型和脊髓损伤患者中，转化生长因子-β1（TGF-β1）的上调和 Smad 信号通路的激活在海绵体纤维化和勃起功能恶化中起着重要作用。已知 Smad 同源物 7（Smad7）可抑制 Smad2 和 Smad3 的磷酸化。
探讨腺病毒编码 Smad7 基因（Ad-Smad7）对 CNI 小鼠模型勃起功能的影响。
将 12 周龄的 C57BL/6J 小鼠分为 7 组：假手术组、未治疗的 CNI 组，以及接受单次海绵体内注射腺病毒编码 LacZ（1×10(8)病毒颗粒[vp]/20μL）或腺病毒编码 Smad7（Ad-Smad7；1×10(7)、1×10(8)、2×10(8)或 1×10(9)vp/20μL）的 CNI 组。
双侧海绵体神经挤压及治疗后 2 周，通过海绵体神经电刺激测量勃起功能。采集阴茎进行组织学检查和 Western blot 分析。
在接受 1×10(8)vp 的 Ad-Smad7 治疗的 CNI 小鼠中，观察到最高的勃起反应，可达假对照值的 82-85%。Ad-Smad7 的局部递送显著降低了内皮细胞凋亡和细胞外基质蛋白的产生，包括纤溶酶原激活物抑制剂-1、纤维连接蛋白、胶原 I 和胶原 IV，并诱导 CNI 小鼠海绵体组织中内皮型一氧化氮合酶磷酸化。
腺病毒介导的 Smad7 基因转移通过增强内皮细胞功能和抗纤维化作用成功恢复了勃起功能。这些发现表明，通过使用 Smad7 抑制 TGF-β 信号通路可能是治疗根治性前列腺切除术后 ED 的一种有前途的治疗策略。
