Abstract
Mechanical forces and biochemical stimuli may interact to regulate cellular responses. In this study, we tested the hypothesis that very small mechanical strains interact with growth factors in the regulation of matrix metalloproteinase (MMP)-1. Human vascular smooth muscle cells (VSMCs) were cultured on a precoated silicone membrane in a device that imposes a highly uniform biaxial strain. VSMCs cultured on fibronectin were treated with cyclic 1-Hz strains of 0, 1, or 4%, and MMPs were assayed by Western analysis or gelatin zymography. Small strains did not induce MMP-1 in VSMCs, but strain was a potent inhibitor of platelet-derived growth factor (PDGF)- or tumor necrosis factor-alpha-induced synthesis of MMP-1. In contrast, MMP-2 and TIMP-2 levels were not changed by PDGF and/or mechanical strain. VSMCs strained on the 120-kDa chymotryptic fragment of fibronectin or RGD peptides suppressed PDGF-induced expression of MMP-1, indicating that this effect is not mediated by the heparin-binding domain or connecting segment-1 of fibronectin. Northern analysis of ets-1, a transcriptional activator of MMP-1 expression, showed that strain down-regulated ets-1 expression, whereas c-fos expression was augmented. Thus, small deformations can selectively suppress MMP-1 synthesis by VSMCs, demonstrating the exquisite sensitivity of the cell to mechanical stimuli.
Highlights
In the vessel wall as well as in other tissues, adaptation occurs through constant cellular migration, proliferation, and death and extracellular matrix synthesis and degradation
Strain Regulates matrix metalloproteinase (MMP)-1 Secretion by vascular smooth muscle cells (VSMCs)—We first evaluated the effect of mechanical strain on MMP-1 synthesis by VSMCs plated on intact FN
platelet-derived growth factor (PDGF) induced MMP-1 in VSMCs plated on 120-kDa chymotryptic fragment of fibronectin (120FN) (5.2 Ϯ 1.9-fold, n ϭ 3), and 1 and 4% cyclic mechanical strains suppressed PDGF-induced MMP-1 by 37 Ϯ 15% and 50 Ϯ 23%, respectively (Fig. 1B)
Summary
In the vessel wall as well as in other tissues, adaptation occurs through constant cellular migration, proliferation, and death and extracellular matrix synthesis and degradation. Several recent lines of evidence suggest that mechanotransduction through the extracellular matrix may regulate secretion of MMPs. First, James et al [15] reported that direct mechanical wounding of a cellular monolayer of VSMCs induces MMP expression. PDGF induced MMP-1 in VSMCs plated on 120FN (5.2 Ϯ 1.9-fold, n ϭ 3), and 1 and 4% cyclic mechanical strains suppressed PDGF-induced MMP-1 by 37 Ϯ 15% and 50 Ϯ 23%, respectively (Fig. 1B).
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