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J. Biol. Chem., Vol. 280, Issue 47, 39474-39484, November 25, 2005

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Rac1 Is Essential for Platelet Lamellipodia Formation and Aggregate Stability under Flow^*

Owen J. T. McCarty1, Mark K. Larson, Jocelyn M. Auger, Neena Kalia, Ben T. Atkinson, Andrew C. Pearce, Sandra Ruf¶, Robert B. Henderson¶, Victor L. J. Tybulewicz¶, Laura M. Machesky, and Steve P. Watson

From the Centre for Cardiovascular Sciences, the Institute of Biomedical Research, and the School of Biosciences, University of Birmingham, Birmingham B15 2TT and ^¶Division of Immune Cell Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom

The role of Rac family proteins in platelet spreading on matrix proteins under static and flow conditions has been investigated by using Rac-deficient platelets. Murine platelets form filopodia and undergo limited spreading on fibrinogen independent of Rac1 and Rac2. In the presence of thrombin, marked lamellipodia formation is observed on fibrinogen, which is abrogated in the absence of Rac1. However, Rac1 is not required for thrombin-induced aggregation or elevation of F-actin levels. Formation of lamellipodia on collagen and laminin is also Rac1-dependent. Analysis of platelet adhesion dynamics on collagen under flow conditions in vitro revealed that Rac1 is required for platelet aggregate stability at arterial rates of shear, as evidenced by a dramatic increase in platelet embolization. Furthermore, studies employing intravital microscopy demonstrated that Rac1 plays a critical role in the development of stable thrombi at sites of vascular injury in vivo. Thus, our data demonstrated that Rac1 is essential for lamellipodia formation in platelets and indicated that Rac1 is required for aggregate integrity leading to thrombus formation under physiologically relevant levels of shear both in vitro and in vivo.

Received for publication, April 28, 2005 , and in revised form, September 29, 2005.

^* This work was supported in part by the Wellcome Trust, British Heart Foundation, and Medical Research Council. 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.

The on-line version of this article (available at http://www.jbc.org) contains Video 1, which shows the dynamics of thrombin-stimulated wild-type murine platelets spreading on fibrinogen; Video 2, which shows the dynamics of thrombin-stimulated Rac1^-/-Rac2^-/- murine platelets spreading on fibrinogen; and supplemental Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Biomedical Engineering, Oregon Health & Science University, 20000 NW Walker Rd., Portland, OR 97006. Tel.: 503-748-1419; Fax: 503-748-7038; E-mail: mccartyo{at}ohsu.edu.

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