Role of PECAM-1 in arteriogenesis and specification of preexisting collaterals.
Role of PECAM-1 in arteriogenesis and specification of preexisting collaterals.
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DOI：
10.1161/circresaha.110.229955
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发表时间：
2010-11-26
影响因子：
20.1
通讯作者：
Tzima E
中科院分区：
文献类型：
--
作者：
Chen Z;Rubin J;Tzima E
响应于闭塞而改变的血流引起的血流动力学力导致侧枝重塑和动脉生成的诱导。先前的研究表明，血小板内皮细胞粘附分子-1 (PECAM-1) 是介导内皮细胞 (EC) 对剪切应力反应的机械感觉复合物的组成部分。我们假设 PECAM-1 在动脉生成和侧枝重塑中发挥重要作用。 PECAM-1 敲除 (KO) 和野生型同窝小鼠接受股动脉结扎。令人惊讶的是，手术后 KO 小鼠的组织灌注和侧支依赖性血流量显着增加。组织学证实 KO 小鼠中先前存在的侧支循环更大。此外，由于剪切应力诱导的信号传导（包括 NF-κB 通路的激活和炎症细胞积累）的缺陷，KO 小鼠表现出后肢缺血后的灌注恢复迟缓和侧枝重塑减少。部分恢复与在缺乏 PECAM-1 的情况下对周壁张力的正常反应相关，肝配蛋白 B2 和 MCP-1（两种拉伸诱导的动脉生成调节剂）在体外和体内的上调证明了这一点。我们的研究结果表明 PECAM-1 在动脉生成和侧支重塑中发挥新作用。此外，我们确定 PECAM-1 是第一个决定预先存在的侧支直径的分子。
Hemodymic forces caused by the altered blood flow in response to an occlusion lead to the induction of collateral remodeling and arteriogenesis. Previous work showed that platelet endothelial cell adhesion molecule-1 (PECAM-1) is a component of a mechanosensorycomplex that mediates endothelial cell (EC) responses to shearstress. We hypothesized that PECAM-1 plays an important role in arteriogenesis and collateral remodeling. PECAM-1 knockout (KO) and wild-type littermates underwent femoral artery ligation. Surprisingly, tissue perfusion and collateral-dependent blood flow were significantly increased in the KO mice immediately after surgery. Histology confirmed larger caliber of preexisting collaterals in the KO mice. Additionally, KO mice showed blunted recovery of perfusion from hindlimb ischemia and reduced collateral remodeling, due to deficits in shear stress-induced signaling, including activation of the NF-κB pathway and inflammatory cell accumulation. Partial recovery was associated with normal responses to circumferential wall tension in the absence of PECAM-1, as evidenced by the upregulation of ephrin B2 and MCP-1, two stretch-induced regulators of arteriogenesis, both in vitro and in vivo. Our findings suggest a novel role for PECAM-1 in arteriogenesis and collateral remodeling. Furthermore, we identify PECAM-1 as the first molecule that determines preexisting collateral diameter.