Nitric oxide synthase modulates angiogenesis in response to tissue ischemia
Nitric oxide synthase modulates angiogenesis in response to tissue ischemia
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DOI：
10.1172/jci1560
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发表时间：
1998-06-01
影响因子：
15.9
通讯作者：
Isner, JM
中科院分区：
文献类型：
--
作者：
Murohara, T;Asahara, T;Isner, JM
我们在两种动物模型中测试了内皮型一氧化氮合酶（eNOS）调节血管生成的假设，其中治疗性血管生成被表征为对组织缺血的代偿性反应。我们首先向手术诱导的后肢缺血的正常兔施用L-精氨酸，先前显示其增加内源性NO的产生，与安慰剂治疗的对照组相比，通过饮食补充L-精氨酸显著改善缺血后肢的血管生成;缺血肢体中血管造影明显的血管分布，肢体灌注的血液动力学指标，毛细血管密度，和血管反应性在侧支血管依赖性缺血肢体都改善了口服L-精氨酸补充。使用手术诱导的后肢缺血的小鼠模型来研究靶向破坏编码ENOS的基因对血管生成的影响。通过激光多普勒血流分析或毛细血管密度测量，与野生型对照组相比，eNOS（-/-）小鼠缺血后肢的血管生成显著受损。eNOS（-/-）小鼠中受损的血管生成没有通过施用血管内皮生长因子（VEGF）得到改善，这表明eNOS在VEGF下游起作用。因此，（a）eNOS是体内血管生成的下游介质，和（B）通过L-精氨酸补充促进eNOS活性加速体内血管生成。这些发现表明，内皮NO合成缺陷可能限制动脉粥样硬化相关内皮功能障碍患者的血管生成，并且口服L-精氨酸补充剂构成了加速晚期血管阻塞患者血管生成的潜在治疗策略。
We tested the hypothesis that endothelial nitric oxide synthase (eNOS) modulates angiogenesis in two animal models in which therapeutic angiogenesis has been characterized as a compensatory response to tissue ischemia, We first administered L-arginine, previously shown to augment endogenous production of NO, to normal rabbits with operatively induced hindlimb ischemia, Angiogenesis in the ischemic hindlimb was significantly improved by dietary supplementation with L-arginine, compared to placebo-treated Controls; angiographically evident vascularity in the ischemic limb, hemodynamic indices of limb perfusion, capillary density, and vasomotor reactivity in the collateral vessel-dependent ischemic limb were all improved by oral L-arginine supplementation. A murine model of operatively induced hindlimb ischemia was used to investigate the impact of targeted disruption of the gene encoding for ENOS on angiogenesis. Angiogenesis in the ischemic hindlimb was significantly impaired in eNOS(-/-) mice versus wild-type controls evaluated by either laser Doppler flow analysis or capillary density measurement. Impaired angiogenesis in eNOS(-/-) mice was not improved by administration of vascular endothelial growth factor (VEGF), suggesting that eNOS acts downstream from VEGF, Thus, (a) eNOS is a downstream mediator for in vivo angiogenesis, and (b) promoting eNOS activity by L-arginine supplementation accelerates in vivo angiogenesis, These findings suggest that defective endothelial NO synthesis may limit angiogenesis in patients with endothelial dysfunction related to atherosclerosis, and that oral L-arginine supplementation constitutes a potential therapeutic strategy for accelerating angiogenesis in patients with advanced vascular obstruction.