Therefore, these results suggest that this interplay might control early atherogenesis in vivo. The role of the extracellular matrix as a key regulator of the behavior of advanced atherosclerosis is widely accepted, with ECM remodeling thought to affect both the size and stability of the fibrous atherosclerotic plaque (Katsuda and Kaji, 2003). deposited at atherosclerosis-prone sites before other indicators of atherosclerosis. Ligation of integrin 21 on collagen prevents flow-induced NF-B activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 AZD3759 activation in cells on fibronectin suppresses NF-B activation, suggesting a novel therapeutic strategy for treating atherosclerosis. Introduction Atherosclerotic plaque develops in response to a localized inflammatory reaction in the vessel wall (Ross, 1999). Although known AZD3759 risk factors for atherosclerosis, such as hyperlipidemia, hypertension, diabetes, and smoking, play major functions in the incidence and progression of the disease, these factors are uniform throughout the circulation. The observation that atherosclerotic plaque forms preferentially at sites of disturbed blood flow (VanderLaan et al., 2004) suggests that flow patterns can regulate the chronic inflammation associated with atherogenesis (Caro et al., 1969; Ku et al., 1985; Glagov et al., 1988). In support of this idea, application of prolonged laminar flow to endothelial cells in culture is usually antiinflammatory and atheroprotective, whereas disturbed flow stimulates endothelial cell turnover, expression of prothrombotic and proinflammatory proteins, and altered redox regulation (Topper et al., 1996; Mohan et al., 1997; De Keulenaer et al., 1998; Brooks et al., 2002). These data suggest that disturbed flow patterns initiate the local inflammatory reaction seen during atherosclerosis, with amplification of lesions by humoral risk factors driving progression of the disease. The NF-B family of transcription factors are involved in numerous cellular processes, including differentiation, inflammation, proliferation, and apoptosis, and are postulated to contribute to atherogenesis (Collins and Cybulsky, 2001; Kutuk and Basaga, 2003). Current data implicate NF-B as a key regulator of shear stressCinduced inflammatory gene expression. NF-B dimers, particularly the p50/p65 heterodimer, bind to a shear stress responsive element found in the promoter of several atherogenic genes, including ICAM-1, VCAM-1, and MCP-1 (monocyte chemotactic protein-1), which regulate monocyte recruitment, as well as PDGF, which stimulates easy muscle growth and migration (Resnick et al., 1993; Khachigian et al., 1995; Huo and Ley, 2001). NF-B expression and activity, as well as ICAM-1 and VCAM-1 expression, are elevated in atherosclerosis-prone regions before or in the absence of fatty streak formation, indicating that they are very early events in atherosclerotic progression (Brand et al., 1996; Nakashima et al., 1998; Iiyama et al., 1999; Wilson et al., 2000). In vitro, disturbed shear stimulates prolonged NF-B activation and NF-BCdependent gene expression; in contrast, acute onset of laminar shear stress activates NF-B but only transiently (Lan et al., 1994; Khachigian et al., 1995; Mohan et al., 1997). We hypothesize that these differences in signaling pathways induced by laminar versus disturbed flow are due in part to differences in adaptation mechanisms, such that changes in flow velocity and direction associated with disturbed flow prevents down-regulation of the responses so that signals activated transiently by laminar flow are sustained in disturbed flow. Thus, data from both in vivo and in vitro models suggest that NF-B contributes to the initiation of atherosclerosis by fluid shear stress. Studies in vitro have shown that acute onset of laminar shear triggers conversion of integrins to a high affinity state, followed by their binding to the subendothelial ECM (Tzima et al., 2001). Resultant integrin signaling mediates activation of NF-B through the small GTPase Rac (Tzima et al., 2002). Endothelial cells normally reside on a basement membrane comprised mainly of collagen (Coll) IV and laminin (LN). Coll binds primarily integrins 21 and 11, whereas LN binds mainly 61 and 64 (Belkin and Stepp, Spry1 2000; Heino, 2000). Ligation of these integrins is associated with a quiescent cell phenotype, consistent with the low turnover observed in endothelial cells in vivo (Schwartz and Assoian, 2001). Inflammation or injury can trigger the deposition of transitional ECM proteins such as fibronectin (FN) and fibrinogen (FG) into the subendothelial matrix (Sechler et al., 1998). In endothelial cells, FN primarily ligates 51 whereas AZD3759 FG ligates.