(Hypertension. 2000;36:319.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Mechanical Strain–Induced Extracellular Matrix Production by Human Vascular Smooth Muscle Cells
Role of TGF-ß1
From the Cardiovascular Research Institute, University of Leicester, UK (B.W.); and the Department of Clinical Pharmacology, Austin and Repatriation Medical Centre, Heidleberg, Australia (C.J.O.).
Correspondence to B. Williams, MD, FRCP, Professor of Medicine and Director, Cardiovascular Research Institute, University of Leicester Clinical Sciences Bldg, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, UK. E-mail bw17{at}le.ac.uk
Abstract—Elevated blood pressure imposes increased mechanical stress on the vascular wall, and mechanical strain is a mitogenic stimulus for vascular smooth muscle (VSM) cells. The role of mechanical forces in regulating the production of noncellular material by VSM cells for VSM cells of human origin remains undefined. We thus investigated the effects of chronic cyclical mechanical strain on extracellular matrix (ECM) protein production by cultured human VSM cells. To simulate a blood pressure of 120/80 mm Hg, human VSM cells were repetitively stretched and relaxed by 10% to 16% of their original length with the Flexercell apparatus. Fibronectin and collagen protein concentrations, matrix metalloproteinase (MMP) activity, and transforming growth factor-ß1 (TGF-ß1) mRNA expression by human VSM cells were measured in response to mechanical strain. Exposing human VSM cells to 5 days of chronic cyclical mechanical strain increased fibronectin (+48%, P<0.01) and collagen (+50%, P<0.001) concentrations when compared with cells grown in static conditions. Mechanical strain also increased MMP-2 activity, the predominant matrix-degrading isoform (+11%, P<0.05) in human VSM cells, thus strain-induced ECM accumulation was not due to inhibition of ECM protein degradation. Strain also increased TGF-ß1 mRNA expression and the production of a soluble factor that increased ECM protein production. Moreover, a TGF-ß–blocking antibody inhibited the effect of strain-conditioned media on matrix production by human VSM cells. These results suggest that chronic cyclical mechanical strain can directly modulate the fibrogenic activity of human VSM cells by inducing ECM protein synthesis and MMP activity. This occurs, at least in part, through mechanical strain–induced TGF-ß1 production, a mechanism that could explain the increased vascular ECM deposition in hypertension.
Key Words: muscle, smooth, vascular • extracellular matrix • transforming growth factors
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