Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury.
Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury.
复制标题
DOI：
10.1161/circulationaha.109.887695
复制
发表时间：
2010-02-02
期刊：
影响因子：
37.8
通讯作者：
Otterbein LE
中科院分区：
文献类型：
--
作者：
Wegiel B;Gallo DJ;Raman KG;Karlsson JM;Ozanich B;Chin BY;Tzeng E;Ahmad S;Ahmed A;Baty CJ;Otterbein LE
一氧化碳（CO）已成为一种血管内稳态分子，通过对血管平滑肌细胞（VSMC）的抗增殖作用防止球囊血管成形术诱导的狭窄。尚未评价CO对再内皮化的影响。在啮齿动物颈动脉损伤模型中，暴露于CO对EC和VSMC增殖具有完全相反的影响。与阻断VSMC生长相反，作为气体或作为CO释放分子（CORM）施用的CO在体外增强EC的增殖和运动性大于50%，与空气对照相比，并且在体内加速损伤后第4天与空气处理的动物中第6天的裸露动脉的再内皮化。CO通过RhoA的快速激活，随后Akt的下游磷酸化，eNOS磷酸化和EC产生的NO增加60%来增强EC增殖。CO通过视网膜母细胞瘤（Rb）的磷酸化驱动细胞周期进程，Rb的磷酸化部分依赖于eNOS产生的一氧化氮（NO）。类似地，体内内皮修复需要骨髓来源的EC祖细胞（EPC）的NO依赖性动员，其中CO显示动员的GFP-Tie-2阳性EPC的数量相对于对照增加4倍，并且在损伤部位处分化的GFP-Tie-2阳性EC相应地加速沉积。在enos−/−小鼠中，CO在增强EC修复和随后内膜增生的发展方面无效。总的来说，我们的数据表明，一氧化碳加速EC增殖和血管修复依赖于NO的产生和增强骨髓来源的内皮祖细胞的招聘。
Carbon monoxide (CO) has emerged as a vascular homeostatic molecule that prevents balloon-angioplasty-induced stenosis via anti-proliferative effects on vascular smooth muscle cells (VSMC). The effects of CO on re-endothelialization have not been evaluated. Exposure to CO has diametrically opposite effects on EC and VSMC proliferation in rodent models of carotid injury. In contrast to blocking VSMC growth, CO administered as a gas or as a CO releasing molecule (CORM) enhances proliferation and motility of EC in vitro greater then 50% vs air controls, and in vivo accelerates re-endothelialization of the denuded artery by day 4 after injury versus day 6 in air-treated animals. CO enhanced EC proliferation via rapid activation of RhoA followed by downstream phosphorylation of Akt, eNOS phosphorylation and a 60% increase in NO generation by the EC. CO drives cell cycle progression through phosphorylation of retinoblastoma (Rb), which is in part dependent on eNOS-generated nitric oxide (NO). Similarly, endothelial repair in vivo requires NO-dependent mobilization of bone marrow-derived EC progenitors (EPC) where CO showed a 4-fold increase in the number of mobilized GFP-Tie-2 positive EPC versus control with a corresponding accelerated deposition of differentiated GFP-Tie-2 positive EC at the site of injury. CO was ineffective in augmenting EC repair and the ensuing development of intimal hyperplasia in enos−/− mice. Collectively our data demonstrate that CO accelerates EC proliferation and vessel repair dependent on NO generation and enhanced recruitment of bone marrow-derived endothelial progenitor cells.