Atherosclerotic plaques, which develop in response to a localized inflammatory response, occur at regions of disturbed blood flow. Fluid shear stress stimulates the binding of endothelial cell integrins to the subendothelial extracellular matrix (ECM), leading to activation of the nuclear factor-κB (NF-κB) signaling pathway and transcription of target genes. Noting that endothelial cells express multiple integrins that bind to matrix proteins and that inflammation promotes the deposition of fibronectin and fibrinogen into the subendothelial ECM, Orr et al. found that changes in subendothelial matrix composition and activation of NF-κB target genes occurred at regions of disturbed flow in vivo before other atherosclerotic changes and were most pronounced in atherosclerosis-prone mice fed a high-fat diet. Fluid shear stress promoted phosphorylation and translocation to the nucleus of NF-κB in bovine aortic endothelial cells cultured on fibrinogen or fibronectin. In contrast, shear stress, acting through integrin α2β1, promoted activation of the p38 protein kinase in cells grown on collagen, leading to reduced NF-κB activation. Intriguingly, NF-κB activation in cells grown on fibronectin could be blocked by treatment with a peptide that alters matrix structure and stimulates p38, suggesting that modification of the ECM with external factors (and localized activation of p38 at integrin adhesion sites) could provide a novel approach to treating atherosclerosis. — EMA
J. Cell Biol. 169, 191 (2005).