Shear stress-induced activation of Tie2-dependent signaling pathway enhances reendothelialization capacity of early endothelial progenitor cells
Shear stress-induced activation of Tie2-dependent signaling pathway enhances reendothelialization capacity of early endothelial progenitor cells
复制标题
剪切应力诱导的 Tie2 依赖性信号通路激活增强了早期内皮祖细胞的再内皮化能力。
DOI：
10.1016/j.yjmcc.2012.01.019
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发表时间：
2012-05-01
影响因子：
5
通讯作者：
Tao, Jun
中科院分区：
文献类型：
--
作者：
Yang, Zhen;Xia, Wen-Hao;Tao, Jun
尽管内皮祖细胞（endothelial progenitor cells，EPCs）在动脉损伤后的内皮修复中起着关键作用，而切应力对EPCs的作用也是有利的，但EPCs对内皮完整性影响的分子机制以及切应力对EPCs信号转导的调控仍有待进一步研究。在这里，我们研究了层流剪切应力对酪氨酸激酶与免疫球蛋白和表皮生长因子同源结构域2（Tie 2）依赖的信号传导的影响及其与人早期EPCs体内再内皮化能力的关系。用剪切应力处理人早期EPCs。剪切应力以剂量依赖的方式增加血管生成素-2（Ang 2）诱导的EPCs迁移，粘附和增殖活性。切应力处理的内皮祖细胞移植促进裸鼠颈动脉损伤模型的体内再内皮化。与此同时，内皮祖细胞Tie 2和Akt的磷酸化水平在剪切应力作用下显著增强。Tie 2基因敲低或Akt抑制可显著抑制内皮祖细胞Akt和内皮型一氧化氮合酶（eNOS）的磷酸化。阻断Tie 2/PI 3 K/Akt/eNOS信号通路后，切应力对EPCs体外功能和体内再内皮化能力的影响均明显受到抑制。本研究首次证实Tie 2/PI 3 k/Akt/eNOS信号通路至少部分参与了内皮祖细胞介导的动脉损伤后再内皮化过程。剪切应力诱导的Tie 2依赖性信号转导的上调有助于增强人EPCs的体内再内皮化能力。(c)2012爱思唯尔有限公司保留所有权利。
Although endothelial progenitor cells (EPCs) play a pivotal role in the endothelial repair following arterial injury and shear stress has a beneficial effect on EPCs, however, the molecular mechanism underlying the influence of EPCs on the endothelial integrity and the regulation of shear stress on the EPC signaling remained to be studied. Here, we investigated the effects of laminar shear stress on the tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2 (Tie2)-dependent signaling and its relation to in vivo reendothelialization capacity of human early EPCs. The human early EPCs were treated with shear stress. Shear stress in a dose-dependent manner increased angiopoietin-2 (Ang2)-induced migratory, adhesive and proliferatory activities of EPCs. Transplantation of EPCs treated by shear stress facilitated in vivo reendothelialization in nude mouse model of carotid artery injury. In parallel, the phosphorylation of Tie2 and Akt of EPCs in response to shear stress was significantly enhanced. With treatment of Tie2 knockdown or Akt inhibition, shear stress-induced phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) of EPCs was markedly suppressed. After Tie2/PI3K/Akt/eNOS signaling was blocked, the effects of shear stress on in vitro function and in vivo reendothelialization capacity of EPCs were significantly inhibited. The present findings demonstrate for the first time that Tie2/PI3k/Akt/eNOS signaling pathway is, at least in part, involved in the EPCs-mediated reendothelialization after arterial injury. The upregulation of shear stress-induced Tie2-dependent signaling contributes to enhanced in vivo reendothelialization capacity of human EPCs. (c) 2012 Elsevier Ltd. All rights reserved.