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Originally published In Press as doi:10.1074/jbc.M200661200 on February 5, 2002

J. Biol. Chem., Vol. 277, Issue 17, 14738-14746, April 26, 2002
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RhoA Sustains Integrin alpha IIbbeta 3 Adhesion Contacts under High Shear*

Simone M. SchoenwaelderDagger , Sascha C. Hughan§, Karen Boniface, Sujanie Fernando, Melissa Holdsworth, Philip E. Thompson, Hatem H. Salem, and Shaun P. Jackson

From the Department of Medicine, Australian Centre for Blood Diseases, Monash University, Box Hill Hospital, Arnold St., Box Hill, Victoria 3128, Australia

The small GTPase RhoA modulates the adhesive nature of many cell types; however, despite high levels of expression in platelets, there is currently limited evidence for an important role for this small GTPase in regulating platelet adhesion processes. In this study, we have examined the role of RhoA in regulating the adhesive function of the major platelet integrin, alpha IIbbeta 3. Our studies demonstrate that activation of RhoA occurs as a general feature of platelet activation in response to soluble agonists (thrombin, ADP, U46619, collagen), immobilized matrices (von Willebrand factor (vWf), fibrinogen) and high shear stress. Blocking the ligand binding function of integrin alpha IIbbeta 3, by pretreating platelets with c7E3 Fab, demonstrated the existence of integrin alpha IIbbeta 3-dependent and -independent mechanisms regulating RhoA activation. Inhibition of RhoA (C3 exoenzyme) or its downstream effector Rho kinase (Y27632) had no effect on integrin alpha IIbbeta 3 activation induced by soluble agonists or adhesive substrates, however, both inhibitors reduced shear-dependent platelet adhesion on immobilized vWf and shear-induced platelet aggregation in suspension. Detailed analysis of the sequential adhesive steps required for stable platelet adhesion on a vWf matrix under shear conditions revealed that RhoA did not regulate platelet tethering to vWf or the initial formation of integrin alpha IIbbeta 3 adhesion contacts but played a major role in sustaining stable platelet-matrix interactions. These studies define a critical role for RhoA in regulating the stability of integrin alpha IIbbeta 3 adhesion contacts under conditions of high shear stress.

* This work was supported in part by grants from the National Health and Medical Research Council (NHMRC) of Australia and the National Heart Foundation of Australia.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of an NHMRC R. D. Wright Fellowship and a Monash University (Australia) Logan Fellowship. To whom correspondence should be addressed: Dept. of Medicine, Monash University, 5th Level, Clive Ward Bldg., Box Hill Hospital, Arnold Street, Box Hill, Victoria 3128, Australia. Tel.: 61-3-9895-0350; Fax: 61-3-9895-0332; E-mail: Simone.Schoenwaelder@med.monash.edu.au.

§ Recipient of the Australian Post-Graduate Research Award.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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