Enhancement of ischemia-induced angiogenesis by eNOS overexpression (Retracted Article)
Enhancement of ischemia-induced angiogenesis by eNOS overexpression (Retracted Article)
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DOI：
10.1161/01.hyp.0000053552.86367.12
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发表时间：
2003-01-01
期刊：
影响因子：
8.3
通讯作者：
Iwasaka, T
中科院分区：
文献类型：
--
作者：
Amano, K;Matsubara, H;Iwasaka, T
内皮细胞一氧化氮（NO）持续过度表达是否发挥血管生成作用仍不确定。我们在过度表达内皮NO合酶的转基因小鼠（eNOS-Tg）中手术诱导后肢缺血，并研究了新毛细血管形成、缺血诱导的血管内皮生长因子（VEGF）表达、cGMP积累和Akt/PKB信号传导。激光多普勒成像显示，与野生型小鼠相比，eNOS-Tg小鼠缺血肢体的血液灌注恢复显著增加（增加44%）。血管造影显示eNOS-Tg小鼠的基础和缺血诱导的侧支血管形成显著增加。eNOS-Tg小鼠的基础毛细血管密度和组织cGMP水平增加（分别为野生型小鼠的1.8倍和1.6倍）。eNOS-Tg小鼠中缺血诱导的新毛细血管形成和cGMP积累显著增加（分别为缺血前水平的3.6倍和4.1倍），而野生型小鼠中的这些则少得多（分别为1.8倍和1.5倍）。缺血肌肉中的基础和时间依赖性VEGF表达在eNOS-Tg和野生型小鼠之间没有差异。基础和VEGF介导的Akt磷酸化在eNOS-Tg和野生型小鼠之间是相似的。主动脉基础eNOS表达增加了3.3倍，与缺血前水平（4.2倍）相比，在eNOS-Tg的动脉瘤中VEGF介导的eNOS磷酸化明显诱导，而在野生型小鼠中观察到的变化要小得多（增加1.8倍）。我们的研究表明，eNOS蛋白的过度表达导致组织缺血时新毛细血管形成显著增加，而不影响缺血诱导的VEGF表达或VEGF介导的Akt磷酸化。
It remains undetermined whether continuous endothelial nitric oxide (NO) overexpression exerts angiogenic action. We surgically induced hindlimb ischemia in transgenic mice overexpressing endothelial NO synthase in the endothelium (eNOS-Tg) and studied neocapillary formation, ischemia-induced vascular endothelial growth factor (VEGF) expression, cGMP accumulation, and Akt/PKB signaling. Laser Doppler imaging revealed a markedly increased recovery of blood perfusion in ischemic limbs of eNOS-Tg mice (44% increase) compared with that in wild-type mice. Angiography showed a marked increase in basal and ischemia-induced collateral vessel formation in eNOS-Tg mice. Basal capillary densities and tissue cGMP levels were increased in eNOS-Tg mice (1.8-fold and 1.6-fold versus wild-type mice, respectively). Ischemia-induced neocapillary formation and cGMP accumulation were markedly increased in eNOS-Tg mice (3.6-fold and 4.1-fold versus preischemia levels, respectively), whereas those in wild-type mice were much less (1.8-fold and 1.5-fold, respectively). Basal and time-dependent VEGF expression in ischemic muscles did not differ between eNOS-Tg and wild-type mice. Basal and VEGF-mediated Akt phosphorylation in aortas was similar between eNOS-Tg and wild-type mice. Aortic basal eNOS expression was increased 3.3-fold, and VEGF-mediated eNOS phosphorylation was markedly induced in aortas of eNOS-Tg compared with preischemia levels (4.2-fold), whereas much smaller changes were observed in wild-type mice (1.8-fold increase). Our study demonstrates that overexpression of eNOS protein causes a marked increase in neocapillary formation in response to tissue ischemia without affecting ischemia-induced VEGF expression or VEGF-mediated Akt phosphorylation.