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Published online February 20, 2007
doi:10.1083/jcb.200609008
The Journal of Cell Biology, Vol. 176, No. 5, 719-727
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Orr et al.
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Article

 Matrix-specific p21-activated kinase activation regulates vascular permeability in atherogenesis

A. Wayne Orr1, Rebecca Stockton1, Michael B. Simmers1,2, John M. Sanders1, Ian J. Sarembock1,3, Brett R. Blackman1,2, and Martin Alexander Schwartz1,4,5

1 Robert M. Berne Cardiovascular Research Center, 2 Department of Biomedical Engineering, 3 Department of Internal Medicine, 4 Department of Microbiology, and 5 Mellon Prostate Cancer Research Center, University of Virginia, Charlottesville, VA 22908

Correspondence to Martin Alexander Schwartz: maschwartz{at}virginia.edu

Elevated permeability of the endothelium is thought to be crucial in atherogenesis because it allows circulating lipoproteins to access subendothelial monocytes. Both local hemodynamics and cytokines may govern endothelial permeability in atherosclerotic plaque. We recently found that p21-activated kinase (PAK) regulates endothelial permeability. We now report that onset of fluid flow, atherogenic flow profiles, oxidized LDL, and proatherosclerotic cytokines all stimulate PAK phosphorylation and recruitment to cell–cell junctions. Activation of PAK is higher in cells plated on fibronectin (FN) compared to basement membrane proteins in all cases. In vivo, PAK is activated in atherosclerosis-prone regions of arteries and correlates with FN in the subendothelium. Inhibiting PAK in vivo reduces permeability in atherosclerosis-prone regions. Matrix-specific PAK activation therefore mediates elevated vascular permeability in atherogenesis.

Abbreviations used in this paper: AID, autoinhibitory domain; BAE, bovine aortic endothelial; CCA, common carotid artery; CS, calf serum; FN, fibronectin; ICS, internal carotid sinus; LDL, low-density lipoprotein; MCP-1, monocyte chemotactic protein-1; MG, matrigel; oxLDL, oxidized LDL; PAK, p21-activated kinase; TJ, tight junction; VCAM-1, vascular cell adhesion molecule 1.


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