Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse
Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse
复制标题
DOI：
10.1073/pnas.1403471111
复制
发表时间：
2014-07-01
影响因子：
11.1
通讯作者：
Suh, Jun-Kyu
中科院分区：
文献类型：
--
作者：
Yin, Guo Nan;Choi, Min Ji;Suh, Jun-Kyu
阴茎勃起是一种神经血管现象，勃起功能障碍(ED)主要由血管危险因素或疾病、神经系统异常和激素紊乱引起。糖尿病ED患者常有严重的内皮功能障碍和周围神经损伤，导致对口服磷酸二酯酶-5抑制剂的反应较差。神经损伤诱导蛋白1(Ninsurin 1，Nins1)参与神经炎症过程，并与胚胎时期的血管退行性变有关。在这里，我们证明了在链脲佐菌素诱导的糖尿病小鼠中，通过注射忍者1中和抗体或使用忍者1基因敲除小鼠来抑制忍者1途径，成功地通过促进阴茎血管生成和神经再生恢复了勃起功能。与正常对照组相比，糖尿病大鼠阴茎组织中血管生成素-1(Ang1)表达下调，血管生成素-2(Angiopoietin-2)表达上调，Nins1-Ab可逆转上述变化。用可溶性Tie2抗体或Ang1 siRNA抑制Ang1-Tie2(带Ig的酪氨酸激酶和表皮生长因子同源域-2)信号转导通路，可阻断忍者受体介导的阴茎血管生成和神经再生以及勃起功能的恢复。本研究结果提示，抑制忍者1通路将成为治疗ED的新的治疗策略。
Penile erection is a neurovascular phenomenon, and erectile dysfunction (ED) is caused mainly by vascular risk factors or diseases, neurologic abnormalities, and hormonal disturbances. Men with diabetic ED often have severe endothelial dysfunction and peripheral nerve damage, which result in poor response to oral phosphodiesterase-5 inhibitors. Nerve injury-induced protein 1 (Ninjurin 1, Ninj1) is known to be involved in neuroinflammatory processes and to be related to vascular regression during the embryonic period. Here, we demonstrate in streptozotocin-induced diabetic mice that inhibition of the Ninj1 pathway by administering Ninj1-neutralizing antibody (Ninj1-Ab) or by using Ninj1-knockout mice successfully restored erectile function through enhanced penile angiogenesis and neural regeneration. Angiopoietin-1 (Ang1) expression was down-regulated and angiopoietin-2 expression was up-regulated in the diabetic penis compared with that in controls, and these changes were reversed by treatment with Ninj1-Ab. Ninj1 blockade-mediated penile angiogenesis and neural regeneration as well as recovery of erectile function were abolished by inhibition of Ang1-Tie2 (tyrosine kinase with Ig and epidermal growth factor homology domain-2) signaling with soluble Tie2 antibody or Ang1 siRNA. The present results suggest that inhibition of the Ninj1 pathway will be a novel therapeutic strategy for treating ED.