Journal
JOURNAL OF CELL BIOLOGY
Volume 176, Issue 5, Pages 719-727Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200609008
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Funding
- NHLBI NIH HHS [R01 HL075092, R01 HL066264, 1R01HL66264, R01 HL75092] Funding Source: Medline
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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.
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