Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels
Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels
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DOI：
10.1182/blood-2003-04-1133
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发表时间：
2004-03-15
期刊：
影响因子：
20.3
通讯作者：
Flaumenhaft, R
中科院分区：
文献类型：
--
作者：
Sim, DS;Merrill-Skoloff, G;Flaumenhaft, R
血小板在血管损伤部位的聚集是动脉血栓形成的主要原因.最初血小板聚集成血栓是由血小板粘附受体与受损内皮或内皮下基质上的配体相互作用介导的。然而，细胞内信号在内皮损伤部位初始血小板聚集中的作用是争论的主题。我们已经使用了一种新发现的磷酸二酯酶3A（PDE 3A）抑制剂和充分表征的PDE 3A抑制剂西洛他唑，在体内模型中调节3 '，5'-环磷酸腺苷（cAMP）水平，从而能够对血小板蓄积进行动力学分析。这些研究表明，基础cAMP水平的升高导致血管损伤部位血小板聚集的总体下降。特别是，血小板积累的初始速率受到cAMP升高的抑制。使用活体显微镜对损伤部位的单个血小板的动力学分析表明，cAMP指导血小板附着于血栓和从血栓分离的速率。这些研究表明，循环血小板中的cAMP控制小动脉损伤部位的附着和脱离。因此，在血小板受体参与之前细胞内信号传导机制的状态影响血栓形成期间血小板积聚的速率。(C)2004年，美国血液学会。
Platelet accumulation at sites of vascular Injury Is the primary event In arterial thrombosis. Initial platelet accrual into thrombi is mediated by interactions of platelet adhesion receptors with ligands on the injured endothellum or in the subendothelial matrix. The role of intracellular signals In initial platelet accumulation at sites of endothelial Injury, however, is the subject of debate. We have used a newly discovered inhibitor of phosphodiesterase 3A (PDE3A) and the well-characterized PDE3A inhibitor, cilostazol, to modulate 3',5'-cyclic adenosine monophosphate (cAMP) levels in an in vivo model that enables the kinetic analysis of platelet accumulation. These studies demonstrate that elevation of basal cAMP levels results in an overall decline in platelet accumulation at the site of vascular injury. In particular, the initial rate of accumulation of platelets is inhibited by elevation of cAMP. Analysis of the kinetics of individual platelets at injury sites using intravital microscopy demonstrates that cAMP directs the rate at which platelets attach to and detach from thrombi. These studies demonstrate that cAMP in circulating platelets controls attachment to and detachment from sites of arteriolar injury. Thus, the status of the intracellular signaling machinery prior to engagement of platelet receptors influences the rate of platelet accumulation during thrombus formation. (C) 2004 by The American Society of Hematology.