Synergism between platelet collagen receptors defined using receptor-specific collagen-mimetic peptide substrata in flowing blood
Synergism between platelet collagen receptors defined using receptor-specific collagen-mimetic peptide substrata in flowing blood
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DOI：
10.1182/blood-2010-01-260778
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发表时间：
2010-06-17
期刊：
影响因子：
20.3
通讯作者：
Farndale, Richard W.
中科院分区：
文献类型：
--
作者：
Pugh, Nicholas;Simpson, Anna M. C.;Farndale, Richard W.
血管损伤后，暴露的内皮下胶原蛋白作为血小板粘附和血栓形成的基质。合成的胶原衍生的三螺旋肽，称为胶原相关肽（CRP）、GFOGER和VWF-III，可以分别特异性地结合血小板胶原受体、糖蛋白VI和整合素α（2）β（1）以及血浆血管性血友病因子（VWF）。目前，这3个胶原结合轴的作用已被间接研究。使用这些均匀的肽底物，而不是胶原纤维，提供了对每个轴的独立控制。在这里，我们使用共聚焦成像和新的图像分析技术，以研究在流动条件下血栓形成过程中血小板结合和活化的受体-配体接合的影响。在低剪切（100 s（-1）和300 s（-1））下，血栓形成需要GFOGER和CRP。在1000 s（-1）时，CRP或GFOGER与VWF-III的组合诱导了相当的血栓形成，VWF-III在所有剪切速率下都增加了血栓沉积，在3000 s（-1）时是不可或缺的。CRP和VWF-III的组合足以支持3000 s（-1）时的广泛血小板沉积，GFOGER的额外作用轻微。在特异性受体阻断或使用改变比例的肽后测量血栓高度表明糖蛋白VI的信号传导作用而不是粘附作用，主要是α 2 β 1和VWF轴的粘附作用。（血。2010;115（24）：5069-5079）
Exposed subendothelial collagen acts as a substrate for platelet adhesion and thrombus formation after vascular injury. Synthetic collagen-derived triple-helical peptides, designated collagen-related peptide (CRP), GFOGER, and VWF-III, can specifically engage the platelet collagen receptors, glycoprotein VI and integrin alpha(2)beta(1), and plasma von Willebrand factor (VWF), respectively. Hitherto, the role of these 3 collagen-binding axes has been studied indirectly. Use of these uniform peptide substrates, rather than collagen fibers, provides independent control of each axis. Here, we use confocal imaging and novel image analysis techniques to investigate the effects of receptor-ligand engagement on platelet binding and activation during thrombus formation under flow conditions. At low shear (100s(-1) and 300s(-1)), both GFOGER and CRP are required for thrombus formation. At 1000s(-1), a combination of either CRP or GFOGER with VWF-III induces comparable thrombus formation, and VWF-III increases thrombus deposition at all shear rates, being indispensable at 3000s(-1). A combination of CRP and VWF-III is sufficient to support extensive platelet deposition at 3000s(-1), with slight additional effect of GFOGER. Measurement of thrombus height after specific receptor blockade or use of altered proportions of peptides indicates a signaling rather than adhesive role for glycoprotein VI, and primarily adhesive roles for both alpha(2)beta(1) and the VWF axis. (Blood. 2010;115(24):5069-5079)