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Published 28 April 2003. doi:10.1083/jcb.200210135
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© The Rockefeller University Press, 0021-9525/2003/4/429 $5.00
The Journal of Cell Biology, Volume 161, Number 2, 429-439

Article

 Shear stress–induced endothelial cell polarization is mediated by Rho and Rac but not Cdc42 or PI 3-kinases

Beata Wojciak-Stothard1,2 and Anne J. Ridley1,2

1 Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, London W1W 7BS, UK
2 Department of Biochemistry and Molecular Biology, University College London, London WC1E 68T, UK

Address correspondence to Beata Wojciak-Stothard, Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, 91 Riding House St., London W1W 7BS, UK. Tel.: 44-207-878-4056. Fax: 44-207-878-4040. E-mail: beata{at}ludwig.ucl.ac.uk

Shear stress induces endothelial polarization and migration in the direction of flow accompanied by extensive remodeling of the actin cytoskeleton. The GTPases RhoA, Rac1, and Cdc42 are known to regulate cell shape changes through effects on the cytoskeleton and cell adhesion. We show here that all three GTPases become rapidly activated by shear stress, and that each is important for different aspects of the endothelial response. RhoA was activated within 5 min after stimulation with shear stress and led to cell rounding via Rho-kinase. Subsequently, the cells respread and elongated within the direction of shear stress as RhoA activity returned to baseline and Rac1 and Cdc42 reached peak activation. Cell elongation required Rac1 and Cdc42 but not phosphatidylinositide 3-kinases. Cdc42 and PI3Ks were not required to establish shear stress–induced polarity although they contributed to optimal migration speed. Instead, Rho and Rac1 regulated directionality of cell movement. Inhibition of Rho or Rho-kinase did not affect the cell speed but significantly increased cell displacement. Our results show that endothelial cells reorient in response to shear stress by a two-step process involving Rho-induced depolarization, followed by Rho/Rac-mediated polarization and migration in the direction of flow.

Key Words: Rho GTPases; actin cytoskeleton; Rho-kinase; migration; polarity

* Abbreviations used in this paper: ß-gal, ß-galactosidase; HUVEC, human umbilical vein endothelial cell; MLCK, myosin light chain kinase; PAK, p21-activated kinase; PI3K, phosphatidylinositide 3-kinase.


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