A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo
A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo
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DOI：
10.1084/jem.20020945
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发表时间：
2003-01-06
影响因子：
15.3
通讯作者：
Nieswandt, B
中科院分区：
文献类型：
--
作者：
Massberg, S;Gawaz, M;Nieswandt, B
血管损伤部位的血小板黏附和聚集是止血的关键，但在动脉粥样硬化的情况下可能会导致动脉闭塞，并引发心肌梗死等疾病。目前的一种假说认为，血小板膜糖蛋白(GP)Ib与von Willebrand因子的相互作用将流动的血小板招募到受损的血管壁，在那里内皮下纤维胶原支持它们牢固的黏附和激活。然而，到目前为止，这一假说还没有在体内得到验证。在这里，我们通过小鼠颈动脉的活体荧光显微镜证明，在内皮剥离后，主要的血小板胶原受体GPVI的抑制或缺失可以消除血小板-血管壁的相互作用。出乎意料的是，用单抗JAQ1抑制GPVI后，血小板与内皮下层的结合减少了约89%。此外，在这些条件下，稳定的血小板滞留和聚集实际上被取消了。使用不同的动脉损伤模型，GPVI缺陷小鼠在这些过程中对GPVI的严格要求得到了证实，在GPVI缺陷小鼠中，血小板也无法黏附和聚集在受损的血管壁上。这些发现揭示了GPVI在启动血管损伤部位的血小板附着中的意想不到的作用，并明确地认为血小板-胶原相互作用(通过GPVI)是动脉血栓形成的主要决定因素。
Platelet adhesion and aggregation at sites of vascular injury is crucial for hemostasis but may lead to arterial occlusion in the setting of atherosclerosis and precipitate diseases such as myocardial infarction. A current hypothesis suggests that platelet glycoprotein (GP) Ib interaction with von Willebrand factor recruits flowing platelets to the injured vessel wall, where subendothelial fibrillar collagens support their firm adhesion and activation. However, so far this hypothesis has not been tested in vivo. Here, we demonstrate by intravital fluorescence microscopy of the mouse carotid artery that inhibition or absence of the major platelet collagen receptor, GPVI, abolishes platelet-vessel wall interactions after endothelial denudation. Unexpectedly, inhibition of GPVI by the monoclonal antibody JAQ1 reduced platelet tethering to the subendothelium by similar to89%. In addition, stable arrest and aggregation of platelets was virtually abolished under these conditions. Using different models of arterial injury, the strict requirement for GPVI in these processes was confirmed in GPVI-deficient mice, where platelets also failed to adhere and aggregate on the damaged vessel wall. These findings reveal an unexpected role of GPVI in the initiation of platelet attachment at sites of vascular injury and unequivocally identify platelet-collagen interactions (via GPVI) as the major determinant of arterial thrombus formation.