Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
J Cardiovasc Pharmacol. 2010 Feb;55(2):153-60. doi: 10.1097/FJC.0b013e3181c9556f.
Previous studies showed that targeted endothelial nitric oxide synthase (eNOS) disruption in mice with femoral artery occlusion does not impede and transgenic eNOS overexpression does not stimulate collateral artery growth after femoral artery occlusion, suggesting that nitric oxide from eNOS does not play a role in arteriogenesis. However, pharmacologic nitric oxide synthase inhibition with L-NAME markedly blocks arteriogenesis, suggestive of an important role of nitric oxide. To solve the paradox, we studied targeted deletion of eNOS and of inducible nitric oxide synthase (iNOS) in mice and found that only iNOS knockout could partially inhibit arteriogenesis. However, the combination of eNOS knockout and treatment with the iNOS inhibitor L-NIL completely abolished arteriogenesis. mRNA transcription studies (reverse transcriptase-polymerase chain reaction) performed on collateral arteries of rats showed that eNOS and especially iNOS (but not neural nitric oxide synthase) become upregulated in shear stress-stimulated collateral vessels, which supports the hypothesis that nitric oxide is necessary for arteriogenesis but that iNOS plays an important part. This was strengthened by the observation that the nitric oxide donor DETA NONOate strongly stimulated collateral artery growth, activated perivascular monocytes, and increased proliferation markers. Shear stress-induced nitric oxide may activate the innate immune system and activate iNOS. In conclusion, arteriogenesis is completely dependent on the presence of nitric oxide, a large part of it coming from mononuclear cells.
先前的研究表明，在股动脉闭塞的小鼠中靶向内皮型一氧化氮合酶（eNOS）的破坏不会阻碍侧支动脉生长，而过表达 eNOS 也不会刺激股动脉闭塞后的侧支动脉生长，这表明 eNOS 产生的一氧化氮在动脉生成中不起作用。然而，使用 L-NAME 抑制一氧化氮合酶的药理作用显著阻断了动脉生成，提示一氧化氮具有重要作用。为了解决这一矛盾，我们研究了 eNOS 和诱导型一氧化氮合酶（iNOS）在小鼠中的靶向缺失，发现只有 iNOS 缺失才能部分抑制动脉生成。然而，eNOS 缺失和 iNOS 抑制剂 L-NIL 的联合治疗完全消除了动脉生成。对大鼠侧支血管的 mRNA 转录研究（逆转录-聚合酶链反应）表明，eNOS，特别是 iNOS（但不是神经型一氧化氮合酶）在剪切力刺激的侧支血管中上调，这支持了一氧化氮是动脉生成所必需的，但 iNOS 起重要作用的假设。这一假设得到了以下观察结果的支持：一氧化氮供体 DETA NONOate 强烈刺激侧支动脉生长，激活血管周围单核细胞，并增加增殖标志物。剪切力诱导的一氧化氮可能激活先天免疫系统并激活 iNOS。总之，动脉生成完全依赖于一氧化氮的存在，其中很大一部分来自单核细胞。
