Small Mechanical Strains Selectively Suppress Matrix Metalloproteinase-1 Expression by Human Vascular Smooth Muscle Cells

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-␣-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.

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

“…Whereas in another study, MMP-1 levels have been reported to be increased with cyclic stretching in human vascular smooth muscle cells (107). In other studies, relative MMP-2 levels were demonstrated to be altered as a function of the magnitude of cyclic strain and the duration of the strain (475,519). In a study by Garcia and colleagues (332), it was demonstrated that local alterations in myocardial strain in vivo could alter local MMP levels.…”

“…However, the relative degree of MMP induction is likely to be time and stimulus-type dependent. For example, a small uniform biaxial strain reduced MMP-1 expression in human vascular smooth muscle cells (519). Whereas in another study, MMP-1 levels have been reported to be increased with cyclic stretching in human vascular smooth muscle cells (107).…”

p38 mitogen-activated kinase is a bidirectional regulator of human fibroblast collagenase-1 induction by three-dimensional collagen lattices

“…fl-coll [3], as well as other signals that induce changes in cell morphology and actin reorganization, stimulate MMP-1 expression. The other signals include mechanical strain [4] and direct mechanical wounding [5] in human vascular smooth-muscle cells, exposure to cytochalasin D in human and rabbit synovial fibroblasts [6,7] and specific cell-matrix interactions [8].…”

Mechanical Strain Induces Specific Changes in the Synthesis and Organization of Proteoglycans by Vascular Smooth Muscle Cells

“…These events include induction of several genes that may affect arterial extracellular matrix, including tenascin-C and plaminogen activator inhibitor-1. In addition, small deformations specifically suppress matrix metalloproteinase-1, an enzyme that can initiate degradation of fibrillar collagen (16).…”