Interstitial flow induces MMP-1 expression and vascular SMC migration in collagen I gels via an ERK1/2-dependent and c-Jun-mediated mechanism

Abstract

The migration of vascular smooth muscle cells (SMCs) and fibroblasts into the intima after vascular injury is a central process in vascular lesion formation. The elevation of transmural interstitial flow is also observed after damage to the vascular endothelium. We have previously shown that interstitial flow upregulates matrix metalloproteinase-1 (MMP-1) expression, which in turn promotes SMC and fibroblast migration in collagen I gels. In this study, we investigated further the mechanism of flow-induced MMP-1 expression. An ERK1/2 inhibitor PD-98059 completely abolished interstitial flow-induced SMC migration and MMP-1 expression. Interstitial flow promoted ERK1/2 phosphorylation, whereas PD-98059 abolished flow-induced activation. Silencing ERK1/2 completely abolished MMP-1 expression and SMC migration. In addition, interstitial flow increased the expression of activator protein-1 transcription factors (c-Jun and c-Fos), whereas PD-98059 attenuated flow-induced expression. Knocking down c-jun completely abolished flow-induced MMP-1 expression, whereas silencing c-fos did not affect MMP-1 expression. Taken together, our data indicate that interstitial flow induces MMP-1 expression and SMC migration in collagen I gels via an ERK1/2-dependent and c-Jun-mediated mechanism and suggest that interstitial flow, ERK1/2 MAPK, c-Jun, and MMP-1 may play important roles in SMC migration and neointima formation after vascular injury.

Interstitial Fluid and Lymph Formation and Transport: Physiological Regulation and Roles in Inflammation and Cancer

“…These stresses can be estimated by the hydraulic conductivity K of the interstitium (discussed in section IIID), since the latter is governed by the flow resistance of the solid phase of the material, i.e., the fluid-solid interactions in the pores or at the ECM fiber boundaries (487). In physiologically relevant interstitial flow rates, average shear stresses have been estimated at Ͻ0.1 dyn/cm 2 (423). These are much lower than those found in the blood vasculature, for example, but similar to shear stress estimates in lymph vessels (113,449).…”

“…Interestingly, it was found that superphysiological or pathological levels of interstitial flow, i.e., 3-10 m/s, could induce fibroblast motility through MMP-1 upregulation (423,424) as well as drive myofibroblast differentiation and matrix alignment (325-327) (FIGURE 15). This matrix alignment was more rapid (within 12-24 h after flow onset) than the myofibroblast differentiation (1-5 days).…”

“…This was consistent with other reports of fibroblast-led tumor cell invasion in live imaging studies of the tumor microenvironment (144,243), but showed for the first time how interstitial flow might influence such behaviors. Such a mechanism may also synergize (or compete) with other proposed mechanisms of interstitial flow-enhanced migration via MMP upregulation (423,424) or ECM stress-mediated effects (367).…”

Biomechanical regulation of vascular smooth muscle cell functions: from in vitro to in vivo understanding

“…SS, shear stress; ASMC, aortic smooth muscle cell; TFPI-2, tissue factor pathway inhibitor-2; Dyn, dyn/cm 2 ; PDGF, platelet-derived growth factor; MMP, matrix metalloprotease; HO, haem oxygenase; CO, carbon monoxide; NO, nitric oxide; ERK1/2, extracellular signal-regulated kinase1/2; AKT, protein kinase B; min, minute (or minutes); h, hour (or hours); d, day (or days [17] laminar SS 6 dyn bovine ASMC aligned along the direction of SS [18] physiological SS 12 dyn rat ASMC NO at 12 -24 h SS-suppressed proliferation and migration [19] laminar SS 3, 6 and 9 dyn bovine ASMC high SS inhibits SMC proliferation [20] rsif.royalsocietypublishing.org J. R. Soc. Interface 11: 20130852 c-Jun-mediated signalling [54,56]. The mechanotransduction can be transmitted by HSPGs and ERK1/2 [41].…”

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

“…When compared with smooth muscle cells (SMCs) from normal veins, SMCs from VVs are more dedifferentiated and show increased migration, proliferation, and MMP-2 production, which may contribute to vein wall remodeling and weakening against increased hydrostatic pressure (Xiao et al, 2009). MMP-1 and -9 levels have also been shown to increase human aortic SMC migration (Jin et al, 2008;Shi et al, 2010). MMP-induced ECM proteolysis may modulate cell-matrix adhesion either by removal of sites of adhesion or by exposing a binding site and, in turn, facilitate VSMC migration.…”