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J. Biol. Chem., Vol. 280, Issue 15, 15430-15437, April 15, 2005

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Importance of Temporal Flow Gradients and Integrin _IIb3 Mechanotransduction for Shear Activation of Platelets^*

Isaac Goncalves, Warwick S. Nesbitt, Yuping Yuan, and Shaun P. Jackson

From the Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Educational Precinct, Prahran, Victoria 3181, Australia

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/cm²). 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 _IIb3-dependent and occurred only on a von Willebrand factor substrate, as platelets forming integrin _IIb3 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 _IIb3 calcium responses in terms of its transient nature, its requirement for platelet co-stimulation by the P2Y₁ 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.

Received for publication, September 7, 2004 , and in revised form, January 14, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Australian Centre for Blood Diseases, Dept. of Medicine, Monash University, 6th Floor, Burnet Tower, Commercial Road, Prahran, Victoria 3181, Australia. Tel.: 61-3-9903-0131; Fax: 61-3-9895-0332; E-mail: shaun.jackson{at}med.monash.edu.au

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