Matrix-specific p21-activated kinase activation regulates vascular permeability in atherogenesis.
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.
Orr
A Wayne
AW
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Stockton
Rebecca
R
Simmers
Michael B
MB
Sanders
John M
JM
Sarembock
Ian J
IJ
Blackman
Brett R
BR
Schwartz
Martin Alexander
MA
D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D002199:Capillary Permeability; D002417:Cattle; D016207:Cytokines / Q000494:pharmacology; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000201:enzymology*; D005353:Fibronectins / Q000378:metabolism; D007365:Intercellular Junctions / Q000201:enzymology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D054462:p21-Activated Kinases
D016207:Cytokines; D005353:Fibronectins; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases