Coordination of platelet agonist signaling during the hemostatic response in vivo
Coordination of platelet agonist signaling during the hemostatic response in vivo
复制标题
体内止血反应期间血小板激动剂信号传导的协调
DOI：
10.1182/bloodadvances.2017009498
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发表时间：
2017-12-26
期刊：
影响因子：
7.5
通讯作者：
Stalker, Timothy J.
中科院分区：
文献类型：
--
作者：
Shen, Jian;Sampietro, Sara;Stalker, Timothy J.
止血塞内的局部微环境形成可溶性血小板激动剂的分布，导致血小板活化的梯度。我们先前表明，血管损伤部位的凝血酶活性在空间上受到限制，导致止血塞核心中血小板亚群的强烈激活。相比之下，腺苷59-二磷酸（ADP）/P2 Y（12）信号传导有助于部分活化的松散包装的血小板聚集在覆盖核心的壳中。其他血小板激动剂血栓素A（2）（TxA（2））和肾上腺素对这种分级组织的贡献以前没有显示。通过结合遗传学和药理学方法以及实时活体成像，我们发现TxA（2）信号传导对于壳区的血小板聚集至关重要，并且与ADP/P2 Y（12）无关，但对于凝血酶活性最高的止血塞核心中的完全血小板活化则不需要。相比之下，肾上腺素信号传导即使在P2 Y（12）拮抗剂存在下也是不稳定的。最后，P2 Y（12）和凝血酶双重抑制作用基本上不会比单独抑制凝血酶更能抑制止血栓核心的形成，这进一步证明了凝血酶是该区域血小板活化的主要驱动因素。总之，这些研究首次显示了凝血酶、P2 Y（12）和TxA（2）信号传导在体内止血塞的分层组织形成过程中是如何协调的，并为双重抗血小板治疗对止血和血栓形成的影响提供了新的见解。
The local microenvironment within an evolving hemostatic plug shapes the distribution of soluble platelet agonists, resulting in a gradient of platelet activation. We previously showed that thrombin activity at a site of vascular injury is spatially restricted, resulting in robust activation of a subpopulation of platelets in the hemostatic plug core. In contrast, adenosine 59-diphosphate (ADP)/P2Y(12) signaling contributes to the accumulation of partially activated, loosely packed platelets in a shell overlying the core. The contribution of the additional platelet agonists thromboxane A(2) (TxA(2)) and epinephrine to this hierarchical organization was not previously shown. Using a combination of genetic and pharmacologic approaches coupled with real-time intravital imaging, we show that TxA(2) signaling is critical and nonredundant with ADP/P2Y(12) for platelet accumulation in the shell region but not required for full platelet activation in the hemostatic plug core, where thrombin activity is highest. In contrast, epinephrine signaling is dispensable even in the presence of a P2Y(12) antagonist. Finally, dual P2Y(12) and thrombin inhibition does not substantially inhibit hemostatic plug core formation any more than thrombin inhibition alone, providing further evidence that thrombin is the primary driver of platelet activation in this region. Taken together, these studies show for the first time how thrombin, P2Y(12), and TxA(2) signaling are coordinated during development of a hierarchical organization of hemostatic plugs in vivo and provide novel insights into the impact of dual antiplatelet therapy on hemostasis and thrombosis.