Induction of Endothelial Cell Proliferation by Recombinant and Microparticle-Tissue Factor Involves β1-Integrin and Extracellular Signal Regulated Kinase Activation
Induction of Endothelial Cell Proliferation by Recombinant and Microparticle-Tissue Factor Involves β1-Integrin and Extracellular Signal Regulated Kinase Activation
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DOI：
10.1161/atvbaha.110.211854
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发表时间：
2010-09-01
影响因子：
8.7
通讯作者：
Ettelaie, Camille
中科院分区：
文献类型：
--
作者：
Collier, Mary E. W.;Ettelaie, Camille
微颗粒形式的循环组织因子（TF）水平升高会增加血栓形成的风险。然而，微粒相关TF对血管内皮细胞增殖的任何直接影响尚不清楚。在这项研究中，重组和微粒相关TF对内皮细胞增殖和丝裂原活化蛋白激酶信号传导机制的影响进行了检查。方法和结果-人冠状动脉内皮细胞与脂质化重组全长TF或含TF微粒孵育（50 ~ 200 pmol/L TF）可促进细胞增殖，并以TF依赖的方式诱导细胞外信号调节激酶1磷酸化。使用PD 98059或细胞外信号调节激酶1/2反义寡核苷酸抑制细胞外信号调节激酶1/2或抑制c-Jun N-末端激酶降低重组TF介导的细胞增殖。PD 98059还降低了响应于含TF微粒的细胞增殖。加入FVIIa（5 nmol/L）和FXa（10 nmol/L）或用抑制性抗FVIIa抗体预孵育细胞对TF介导的细胞增殖无额外影响。然而，外源性TF与β 1整合素肽的预孵育，结论-高浓度的重组或微粒相关TF通过激活细胞外信号调节激酶1/2途径刺激内皮细胞增殖，通过一种新的机制介导，需要外源性TF与细胞表面β 1-整联蛋白的相互作用，并且独立于FVIIa。（Arterioscler Thromb Vasc Biol.2010; 30：1810-1817.）
Objective-Increased levels of circulating tissue factor (TF) in the form of microparticles increase the risk of thrombosis. However, any direct influence of microparticle-associated TF on vascular endothelial cell proliferation is not known. In this study, the influence of recombinant and microparticle-associated TF on endothelial cell proliferation and mitogen-activated protein kinase signaling mechanisms was examined.Methods and Results-Incubation of human coronary artery endothelial cells with lipidated recombinant full-length TF, or TF-containing microparticles (50 to 200 pmol/L TF), increased the rate of cell proliferation and induced phosphorylation of extracellular signal regulated kinase 1 in a TF-dependent manner. Inhibition of extracellular signal regulated kinase 1/2 using PD98059 or extracellular signal regulated kinase 1/2 antisense oligonucleotides or inhibition of c-Jun N-terminal kinase reduced recombinant TF-mediated cell proliferation. PD98059 also reduced cell proliferation in response to TF-containing microparticles. Inclusion of FVIIa (5 nmol/L) and FXa (10 nmol/L) or preincubation of cells with an inhibitory anti-FVIIa antibody had no additional influence on TF-mediated cell proliferation. However, preincubation of exogenous TF with a beta 1-integrin peptide (amino acids 579 to 799) reduced TF-mediated proliferation.Conclusion-High concentrations of recombinant or microparticle-associated TF stimulate endothelial cell proliferation through activation of the extracellular signal regulated kinase 1/2 pathway, mediated through a novel mechanism requiring the interaction of exogenous TF with cell surface beta 1-integrin and independent of FVIIa. (Arterioscler Thromb Vasc Biol. 2010; 30: 1810-1817.)