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J. Biol. Chem., Vol. 279, Issue 45, 46621-46630, November 5, 2004

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p21-activated Kinase Regulates Endothelial Permeability through Modulation of Contractility^*

Rebecca A. Stockton, Erik Schaefer, and Martin Alexander Schwartz¶||

From the Cardiovascular Research Center, University of Virginia Health System, Charlottesville, Virginia 22908, BioSource International, Hopkinton, Massachusetts 01748, ^¶Departments of Microbiology and Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908

Endothelial cells lining the vasculature have close cell-cell associations that maintain separation of the blood fluid compartment from surrounding tissues. Permeability is regulated by a variety of growth factors and cytokines and plays a role in numerous physiological and pathological processes. We examined a potential role for the p21-activated kinase (PAK) in the regulation of vascular permeability. In both bovine aortic and human umbilical vein endothelial cells, PAK is phosphorylated on Ser¹⁴¹ during the activation downstream of Rac, and the phosphorylated subfraction translocates to endothelial cell-cell junctions in response to serum, VEGF, bFGF, TNF, histamine, and thrombin. Blocking PAK activation or translocation prevents the increase in permeability across the cell monolayer in response to these factors. Permeability correlates with myosin phosphorylation, formation of actin stress fibers, and the appearance of paracellular pores. Inhibition of myosin phosphorylation blocks the increase in permeability. These data suggest that PAK is a central regulator of endothelial permeability induced by multiple growth factors and cytokines via an effect on cell contractility. PAK may therefore be a suitable drug target for the treatment of pathological conditions where vascular leak is a contributing factor, such as ischemia and inflammation.

Received for publication, August 4, 2004 , and in revised form, August 23, 2004.

^* This research was supported by National Institutes of Health (NIH) Training Grant 5T32 HL-007284-27 through the University of Virginia Cardiovascular Research Center and NIH Grant RO1-GM47214 (to M. A. S.). 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: Cardiovascular Research Ctr., 415 Lane Rd., MR5 Rm. G-111, Charlottesville, VA 22908. Tel.: 434-243-4813; Fax: 434-924-2828; E-mail: maschwartz{at}virginia.edu.

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