Goncalves Isaac, Nesbitt Warwick S, Yuan Yuping, Jackson Shaun P
Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Educational Precinct, Prahran, Victoria 3181, Australia.
J Biol Chem. 2005 Apr 15;280(15):15430-7. doi: 10.1074/jbc.M410235200. Epub 2005 Feb 8.
Disturbances of blood flow play an important role in promoting platelet activation and arterial thrombus formation in stenosed, injured, atherosclerotic arteries. To date, glycoprotein Ib (GPIb) has been considered the primary platelet mechanosensory receptor, responding to increased shear with enhanced adhesive and signaling function. We demonstrate here that von Willebrand factor-GPIb interaction is inefficient at inducing platelet activation even when platelets are exposed to very high wall shear stresses (60 dyn/cm(2)). Rapid platelet activation under flow was only observed under experimental conditions in which transiently adherent platelets were exposed to sudden accelerations in blood flow. Platelet responsiveness to temporal shear gradients was integrin alpha(IIb)beta(3)-dependent and occurred only on a von Willebrand factor substrate, as platelets forming integrin alpha(IIb)beta(3) adhesive contacts with immobilized fibrinogen were unresponsive to sudden increases in shear. The calcium response induced by temporal shear gradients was distinct from previously identified integrin alpha(IIb)beta(3) calcium responses in terms of its transient nature, its requirement for platelet co-stimulation by the P2Y(1) purinergic ADP receptor, and its dependence on the influx of extracellular calcium. Our studies demonstrate a key role for temporal shear gradients in promoting platelet activation. Moreover, they define for the first time the involvement of P2Y receptors in integrin mechanotransduction.
血流紊乱在促进狭窄、损伤、动脉粥样硬化动脉中的血小板活化和动脉血栓形成方面起着重要作用。迄今为止，糖蛋白Ib（GPIb）一直被认为是主要的血小板机械感觉受体，对增加的剪切力作出反应，增强黏附功能和信号传导功能。我们在此证明，即使血小板暴露于非常高的壁面剪切应力（60达因/平方厘米），血管性血友病因子与GPIb的相互作用在诱导血小板活化方面效率低下。仅在实验条件下观察到流动状态下血小板的快速活化，即短暂黏附的血小板暴露于血流的突然加速中。血小板对时间剪切梯度的反应性依赖于整合素α（IIb）β3，并且仅在血管性血友病因子底物上发生，因为与固定化纤维蛋白原形成整合素α（IIb）β3黏附接触的血小板对剪切力的突然增加无反应。时间剪切梯度诱导的钙反应在其短暂性、对P2Y（1）嘌呤能ADP受体共同刺激血小板的需求以及对细胞外钙内流的依赖性方面，与先前确定的整合素α（IIb）β3钙反应不同。我们的研究证明了时间剪切梯度在促进血小板活化中的关键作用。此外，它们首次确定了P2Y受体参与整合素的机械转导。
