Signaling from the Substrate

Abstract

Atherosclerotic plaques, which develop in response to a localized inflammatory response, occur at regions of disturbed blood flow. Fluid shear stress stimulates 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 such as ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1). Noting that endothelial cells express multiple integrins that preferentially bind to various matrix proteins and that inflammation promotes deposition of fibronectin and fibrinogen into the subendothelial ECM, Orr et al. investigated the role of the subendothelial ECM in mediating the response to shear stress. 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 of the NF-κB p65 subunit and NF-κB nuclear translocation in bovine aortic endothelial (BAE) cells cultured on fibrinogen or fibronectin. In contrast, shear stress--acting through integrin α2β1--promoted p38 mitogen-activated protein kinase activation in BAE cells grown on collagen, leading to reduced NF-κB activation. In cells grown on mixed matrices, collagen suppressed fibronectin-dependent NF-κB activation. However, growth on collagen failed to inhibit activation of NF-κB following exposure to tumor necrosis factor α; immunocytochemical analysis indicated that localized activation of p38 at integrin adhesion sites inhibited local--but not global--NF-κB activation. Intriguingly, NF-κB activation in cells grown on fibronectin was blocked by treatment with a fibronectin-derived peptide that alters matrix structure and stimulates p38 activation, which suggests that modification of the subendothelial matrix with external factors could provide a novel approach to treating atherosclerosis. A. W. Orr, J. M. Sanders, M. Bevard, E. Coleman, I. J. Sarembock, M. A. Schwartz, The subendothelial extracellular matrix modulates NF-κB activation by flow: A potential role in atherosclerosis. J. Cell Biol. 169 , 191-202 (2005). [Abstract] [Full Text]