The subendothelial extracellular matrix modulates NF-kappaB activation by flow: a potential role in atherosclerosis.
Atherosclerotic plaque forms in regions of the vasculature exposed to disturbed flow. NF-kappaB activation by fluid flow, leading to expression of target genes such as E-selectin, ICAM-1, and VCAM-1, may regulate early monocyte recruitment and fatty streak formation. Flow-induced NF-kappaB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling. Therefore, we examined the involvement of the extracellular matrix in this process. Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-kappaB in response to flow, cells on collagen or laminin do not. In vivo, fibronectin and fibrinogen are deposited at atherosclerosis-prone sites before other signs of atherosclerosis. Ligation of integrin alpha2beta1 on collagen prevents flow-induced NF-kappaB activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-kappaB activation, suggesting a novel therapeutic strategy for treating atherosclerosis.
Orr
A Wayne
AW
Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
Sanders
John M
JM
Bevard
Melissa
M
Coleman
Elizabeth
E
Sarembock
Ian J
IJ
Schwartz
Martin Alexander
MA
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004032:Diet; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D038982:Integrin alpha2beta1 / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001057:Apolipoproteins E; D038982:Integrin alpha2beta1; D016328:NF-kappa B; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases