SMALL MECHANICAL STRAINS SELECTIVELY SUPPRESS MATRIX METALLOPROTEINASE-1 EXPRESSION BY HUMAN VASCULAR SMOOTH-MUSCLE CELLS

Mechanical forces and biochemical stimuli may interact to regulate cel lular responses, In this study, we tested the hypothesis that very sma ll mechanical strains interact with growth factors in the regulation o f matrix metalloproteinase (MMP)-1. Human vascular smooth muscle cells (VSMCs) were cultured on a precoated silicone membrane in a device th at imposes a highly uniform biaxial strain, VSMCs cultured on fibronec tin were treated with cyclic 1-Hz strains of 0, 1, or 4%, and MMPs wer e assayed by Western analysis or gelatin zymography. Small strains did not induce MMP-1 in VSMCs, but strain was a potent inhibitor of plate let-derived growth factor (PDGF)- or tumor necrosis factor-alpha-induc ed synthesis of MMP-1. In contrast, MMP-2 and TIMP-2 levels were not c hanged 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 mediat ed by the heparin-binding domain or connecting segment-1 of fibronecti n. Northern analysis of ets-1, a transcriptional activator of MMP-1 ex pression, showed that strain down-regulated ets-1 expression, whereas c-fos expression was augmented. Thus, small deformations can selective ly suppress MMP-1 synthesis by VSMCs, demonstrating the exquisite sens itivity of the cell to mechanical stimuli.