The glycoprotein VI phospholipase Cγ2 signaling pathway controls thrombus formation induced by collagen and tissue factor in vitro and in vivo
The glycoprotein VI phospholipase Cγ2 signaling pathway controls thrombus formation induced by collagen and tissue factor in vitro and in vivo
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DOI：
10.1161/01.atv.0000193568.71980.4a
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发表时间：
2005-12-01
影响因子：
8.7
通讯作者：
Heemskerk, JWM
中科院分区：
文献类型：
--
作者：
Munnix, ICA;Strehl, A;Heemskerk, JWM
目的：胶原和组织因子均可作为血栓形成的始动因子。我们研究了在血栓形成过程中，胶原诱导的血小板激活与组织因子触发的凝血相互作用的信号通路。方法和结果：在小鼠血液流经胶原的过程中，血小板暴露于磷脂酰丝氨酸和促凝血活性，而不是黏附，完全依赖于以下信号模块中的每一个：糖蛋白VI(GPVI)、FCR伽马链、Src激酶、接头蛋白LAT和磷脂酶C伽马2(PLC Gamma 2)。在有组织因子存在的血流中，这些信号成分对于血小板聚集和极大地促进纤维蛋白凝块的形成是必不可少的。胶原刺激的凝血酶生成依赖于GPVI、FCR-Gamma链、Src激酶、LAT和PLC-Gamma 2的存在和活性。在FeCl3诱导的小鼠体内血栓形成模型中，这一GPVI途径的生理意义被证明。在小静脉和小动脉中，通过GPVI、FCR-Gamma链和Src激酶的信号通路促进了磷脂酰丝氨酸暴露和富含纤维蛋白的血栓的形成。结论：GPVI-PLC-Gamma 2激活通路在静脉和动脉血栓形成中调节胶原依赖的凝血。
Objective - Both collagen and tissue factor can be initiating factors in thrombus formation. We investigated the signaling pathway of collagen-induced platelet activation in interaction with tissue factor - triggered coagulation during the thrombus-forming process.Methods and Results - In murine blood flowing over collagen, platelet exposure of phosphatidylserine and procoagulant activity, but not adhesion, completely relied on each of the following signaling modules: glycoprotein VI (GPVI), FcR gamma-chain, Src kinases, adaptor protein LAT, and phospholipase C gamma 2 (PLC gamma 2). On flow in the presence of tissue factor, these signaling components were essential for platelet aggregation and greatly enhanced fibrin clot formation. Collagen-stimulated thrombin generation relied on the presence and activity of GPVI, FcR gamma-chain, Src kinase, LAT, and PLC gamma 2. The physiological importance of this GPVI pathway was shown in a FeCl3-induced in vivo murine thrombosis model. In both venules and arterioles, signaling through GPVI, FcR gamma-chain, and Src kinases enhanced the formation of phosphatidylserine-exposing and fibrin-rich thrombi.Conclusions - The GPVI-PLC gamma 2 activation pathway regulates collagen-dependent coagulation in venous and arterial thrombus formation.