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

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-α-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-1expression, 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. 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-α-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-1expression, 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. 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. In stable normal tissues, the rates of these processes are so slow that they may appear almost dormant, whereas in injured or repairing tissues, the processes may all be greatly accelerated. In any wound repair, it is critical that the repaired tissue be sufficiently strong to withstand mechanical forces the tissue may experience. However, while the importance of biochemical mediators such as cytokines and growth factors in tissue repair and homeostasis is clear (1Ross R. Nature. 1993; 362: 801-808Crossref PubMed Scopus (9970) Google Scholar, 2Osol G. J. Vasc. Res. 1995; 32: 275-292Crossref PubMed Scopus (178) Google Scholar, 3Gibbons G.H. Dzau V.J. N. Engl. J. Med. 1994; 330: 1431-1438Crossref PubMed Scopus (1345) Google Scholar), how mechanical forces may regulate tissue structure and repair is less understood. The regulation of the wound repair response by mechanical forces is particularly relevant to the cardiovascular system, which must withstand large dynamic fluctuations in strain. Several studies have shown that mechanical forces exert important regulatory effects on vascular smooth muscle cells (VSMCs), 1The abbreviations used are: VSMCs, vascular smooth muscle cells; PDGF, platelet-derived growth factor; MMP, matrix metalloproteinase; IL-1, interleukin-1; TNF-α, tumor necrosis factor-α; FN, fibronectin; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum. 1The abbreviations used are: VSMCs, vascular smooth muscle cells; PDGF, platelet-derived growth factor; MMP, matrix metalloproteinase; IL-1, interleukin-1; TNF-α, tumor necrosis factor-α; FN, fibronectin; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum. including increased collagen synthesis and cell growth by mechanical strain (4Leung D.Y.M. Glagov S. Mathews M.B. Science. 1976; 191: 475-478Crossref PubMed Scopus (543) Google Scholar, 5Calara F. Ameli S. Hultgardh-Nilsson A. Cercek B. Kupter J. Hedin U. Forrester J. Shah P.K. Nilson J. Arterioscler. Thromb. Vasc. Biol. 1996; 16: 187-193Crossref PubMed Scopus (29) Google Scholar, 6Kolpakov V. Rekhter M.D. Gordon D. Wang W.H. Kulik T.J. Circ. Res. 1995; 77: 823-831Crossref PubMed Scopus (88) Google Scholar). Wilsonet al. (7Wilson E. Mai Q. Sudhir K. Weiss R.H. Ives H.E. J. Cell Biol. 1993; 123: 741-747Crossref PubMed Scopus (337) Google Scholar, 8Wilson E. Sudhir K. Ives H.E. J. Clin. Invest. 1995; 96: 2364-2372Crossref PubMed Scopus (268) Google Scholar) have demonstrated that mechanical strain stimulates a mitogenic response in rat VSMCs through induction of platelet-derived growth factor (PDGF), and this induction is regulated by specific extracellular matrix interactions. Thus, VSMCs may sense mechanical stimuli (mechanotransduction) and change arterial structure. One way VSMCs can change arterial structure is through the matrix metalloproteinases (MMPs). The MMPs are members of a family of enzymes that digest specific components of the extracellular matrix and may play a critical role in tissue repair and remodeling. The enzymatic activity of MMPs is regulated at several levels, including transcription; for example, cytokines such as IL-1, TNF-α, and PDGF induce secretion of MMP proenzymes (9Brenner D.A. O'Hara M. Angel P. Chojkier M.K. Nature. 1989; 337: 661-663Crossref PubMed Scopus (611) Google Scholar, 10Yanagi H. Sasaguri Y. Sugama K. Morimatsu M. Nagase H. Atherosclerosis. 1992; 91: 207-210Abstract Full Text PDF Scopus (89) Google Scholar). These latent proenzymes can then be activated in the extracellular space (11Kleiner Jr., D.E. Stetler-Stevenson W.G. Curr. Opin. Cell Biol. 1993; 5: 891-897Crossref PubMed Scopus (328) Google Scholar, 12Grant G.A. Eisen A.Z. Marmer B.L. Roswit W.T. Goldberg G.I. J. Biol. Chem. 1987; 262: 5886-5889Abstract Full Text PDF PubMed Google Scholar). Finally, the active MMPs may be inhibited by TIMPs (tissue-typeinhibitors of matrix metalloproteinase), specific endogenous inhibitors of the MMPs. Several MMP promoters contain the 12-O-tetradecanoylphorbol-13-acetate response element, which binds AP-1, transcription factor dimeric combinations of c-Fos and c-Jun, as well as polyoma enhancer activator sites (PEA3), which bind the Ets family of transcription factors (13Gutman A. Wasylyk B. EMBO J. 1990; 9: 2241-2246Crossref PubMed Scopus (399) Google Scholar, 14Tremble P. Damsky C.H. Werb Z. J. Cell Biol. 1995; 129: 1707-1720Crossref PubMed Scopus (115) Google Scholar). Several recent lines of evidence suggest that mechanotransduction through the extracellular matrix may regulate secretion of MMPs. First, James et al. (15James T.W. Wagner R. White L.A. Zwolak R.M. Brickerhoff C.E. J. Cell. Physiol. 1993; 157: 427-437Crossref Scopus (86) Google Scholar) reported that direct mechanical wounding of a cellular monolayer of VSMCs induces MMP expression. Second, perturbing the cytoskeleton of rabbit synovial fibroblasts induces MMP expression (16Werb Z. Hembry R.M. Murphy G. Aggeler J. J. Cell Biol. 1986; 102: 697-702Crossref PubMed Scopus (126) Google Scholar). Third, Huhtala et al. (17Huhtala P. Humphries M.J. McCarthy J.B. Tremble P.M. Werb Z. Damsky C.H. J. Cell Biol. 1995; 129: 867-879Crossref PubMed Scopus (369) Google Scholar) have demonstrated that domains of fibronectin (FN) may interact with different integrin subunits to either induce or suppress collagenase (MMP-1) expression in rabbit synovial fibroblast cells. Finally, we and others (18Galis Z.S. Sukhova G.K. Lark M.W. Libby P. J. Clin. Invest. 1995; 94: 2493-2503Crossref Scopus (2192) Google Scholar, 19Lee R.T. Schoen F.J. Loree H.M. Lark M.W. Libby P. Arterioscler. Thromb. Vasc. Biol. 1996; 16: 1070-1073Crossref PubMed Scopus (272) Google Scholar) have observed that, in vivo, MMP-1 is overexpressed at sites of mechanical overload in the diseased artery. Using a mechanical deformation device that applies a highly uniform biaxial strain field over the culture substrate, we explored the hypothesis that mechanical deformations regulate MMP-1 secretion by VSMCs. Surprisingly, we found that very small strains do not induce MMP-1, but abolish induction of MMP-1 by PDGF or TNF-α, demonstrating that mechanical stimuli may potently interact with biochemical signals in regulating extracellular matrix metabolism. DMEM and Ham's F-12 were obtained from BioWhittaker, Inc. Dulbecco's phosphate-buffered saline solution, Hanks' salt solution, fibronectin, 120-kDa chymotryptic fibronectin fragment, GRGDSP peptide, phorbol 12-myristate 13-acetate, and other materials required for tissue culture were purchased from Life Technologies, Inc. Ovalbumin, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, Tris, glycine, sodium chloride, and sodium dodecyl sulfate were obtained from Sigma. PDGF- BB, IL-1α, and TNF-α were from Collaborative Biomedical Products (Bedford, MA), and collagen was from Cell Biomaterials (Palo Alto, CA). Prestained low molecular mass markers and acrylamide gel buffer were purchased from Bio-Rad. α-32PdCTP (3000 Ci/mmol) was purchased from NEN Life Science Products. Human VSMCs were derived from explants of discarded portions of saphenous vein after coronary bypass surgery from Brigham and Women's Hospital. VSMCs were maintained in DMEM, 10% fetal calf serum, and 1% penicillin/streptomycin sulfate. These conditions are selective for growth of smooth muscle cells over endothelial cells (20Gimbrone M.A. Cotran R.S. Lab. Invest. 1975; 33: 16-27PubMed Google Scholar). VSMCs were maintained at 37 °C in 5% CO2 up to passages 6–7 for experiments. Approximately 50% of cells using these techniques stained positively for α-actin. Mechanical deformation was applied to a thin and transparent membrane on which cells were cultured, an approach that produces controlled cellular strain as well as visualization of cells. This device provides a nearly homogeneous biaxial strain profile, i.e. strains that are equal at all locations on the membrane and in all directions (21Schaffer J.L. Rizen M. L'Italien G.J.L. Benbrahim A. Megerman J. Gerstenfeld L.C. Gray M.L. J. Orthop. Res. 1993; 12: 709-719Crossref Scopus (130) Google Scholar). An advantage of this device over some commonly used systems is that it eliminates locations on the substrate that have very high strains (20–30%) in one direction. Each culture dish consists of a plastic (Kynar) cylinder and a circular silicone elastometric membrane, which is the culture surface. The membrane undergoes cyclic tensile deformation as the platen assembly moves sinusoidally with a frequency and amplitude derived by the motor speed and the cam size, respectively. We have previously measured membrane strains with a high resolution video device (22Cheng G.C. Briggs W.H. Gerson D.S. Libby P. Grodzinsky A.J. Gray M.L. Lee R.T. Circ. Res. 1997; 80: 28-36Crossref PubMed Scopus (119) Google Scholar); the cams used for this study gave strains of 1.0 ± 0.1% and 4.2 ± 0.1% (n = 18 different locations for each). The cell culture silicone membrane itself supports negligible adhesion of VSMCs. In these experiments, three different methods of supporting adhesion were used: precoating with intact FN, 120FN (the 120-kDa chymotryptic peptide of FN that the RGD and RGD peptide to or VSMCs were on precoated with of FN, and RGD peptide, was in VSMCs. the of VSMCs to be to mechanical membrane were with FN in of Hanks' for at °C and then with of phosphate-buffered VSMCs were on the membrane dish at a of in of DMEM 10% and VSMCs on the collagen was VSMCs were then with of Hanks' to and with of of DMEM and Ham's F-12 with and for mechanical strain or of was Mechanical strain was then applied at a constant frequency and and mechanical strain. The of RGD peptides with was as by et al. P.K. McCarthy J.B. J. Cell Biol. 1990; PubMed Scopus Google Scholar). of GRGDSP peptides and were and with a mass of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in in the at the were phosphate-buffered saline to and peptides membrane, were by were on a 10% gel and to a membrane in and The membrane was with 5% in buffer and 0.1% for the of collagenase the membrane was with rabbit collagenase of for at 37 °C and with buffer for The to was and with the membrane for with buffer for the membrane was by the Life the of and rabbit and rabbit TIMP-2 of were respectively. of Western was by using the are as the ± from three experiments. were on a 10% gel The gel was in buffer for and then in for to the gel was in buffer and at 37 The activity was shown by with 0.1% 10% and and with 10% and was by the and P. N. 1987; PubMed Scopus Google Scholar). The MMP-1 and were used as of the of the VSMCs were with phorbol 12-myristate for after of was used for the synthesis of by with a CA). of the was by with The for the synthesis of the the sense and The was used as the The for the synthesis of c-fos and a The were by the with α-32PdCTP and the fragment of Northern of was on a gel to a membrane Life and with a The was with Alto, at °C for The membrane was with and for at and with and 0.1% with at °C for The membrane was to at We the effect of mechanical strain on MMP-1 synthesis by VSMCs on intact cells were to 0, 1, and cyclic mechanical strains at in experiments, mechanical strain did not induce MMP-1 expression, whereas MMP-1 ± = Surprisingly, 1% cyclic mechanical strain suppressed ± (n = of PDGF-induced MMP-1 expression, and strain suppressed ± of MMP-1 expression In these in cells were strains of or 4%, and we have previously demonstrated that cellular and fibroblast growth at strains 10% in VSMCs (22Cheng G.C. Briggs W.H. Gerson D.S. Libby P. Grodzinsky A.J. Gray M.L. Lee R.T. Circ. Res. 1997; 80: 28-36Crossref PubMed Scopus (119) Google Scholar). Thus, these that specific regulation and not cellular of MMP-1 synthesis by mechanical deformations these Huhtala et al. (17Huhtala P. Humphries M.J. McCarthy J.B. Tremble P.M. Werb Z. Damsky C.H. J. Cell Biol. 1995; 129: 867-879Crossref PubMed Scopus (369) Google Scholar) have demonstrated that the 120-kDa chymotryptic fragment of fibronectin which the RGD but not contain the connecting segment-1 of fibronectin, can induce MMP-1 secretion by rabbit synovial Thus, that small mechanical strains on intact FN can suppress MMP-1 secretion the hypothesis that mechanical strains suppress MMP-1 secretion through domains of this we VSMCs on a to of adhesion of cells as intact FN of a In to on rabbit synovial VSMCs on 120FN did not induce MMP-1, did mechanical strain induce MMP-1 expression by VSMCs on PDGF MMP-1 in VSMCs on 120FN ± = and and cyclic mechanical strains suppressed PDGF-induced MMP-1 by 37 ± and ± This that strain did not MMP-1 synthesis through adhesion to the connecting segment-1 of In we VSMCs on RGD peptide MMP-1 expression by VSMCs on RGD peptides was to that by VSMCs on intact FN or 120FN ± = to the effects of FN and PDGF MMP-1 expression on RGD but and mechanical strains suppressed ± and ± of PDGF-induced MMP-1 These the that of MMP-1 by small mechanical strains not the connecting segment-1 domain of FN and that mechanical strain through the RGD domain is for this MMPs have expression of the particularly may be of MMP-1 expression 1992; PubMed Scopus Google Scholar). we the expression of MMP-2 and by VSMCs in response to mechanical stimuli and PDGF mechanical strain PDGF changed MMP-2 expression VSMCs on 120FN or RGD peptide levels of MMP-2 of PDGF or mechanical strain and We found activity in VSMCs on FN, but the activity was very with MMP-2 PDGF mechanical strain increased expression 120FN or RGD induction was not observed with intact FN, and PDGF mechanical strain increased expression and These the that all MMPs were down-regulated by mechanical strain. We then explored the effects of mechanical strain on synthesis of and endogenous inhibitors of FN, expression was whereas PDGF expression by ± (n = to the effect of mechanical strain on MMP-1 strains of and suppressed PDGF-induced expression by ± and ± VSMCs were on expression was to that of VSMCs on intact FN, and PDGF expression by ± (n = mechanical strain did not expression, but and strains suppressed PDGF-induced expression by ± and ± VSMCs were cultured on to RGD expression was not but PDGF expression by ± RGD and mechanical strains suppressed PDGF-induced expression by ± and ± These showed that the effect of strain on regulation by VSMCs on intact FN, or RGD peptides was to the effect of strain on MMP-1 In to the effects of mechanical strain on MMP-1 and expression, the expression of the specific inhibitor of by VSMCs cultured on FN was not changed by PDGF or mechanical strain VSMCs were cultured on 120FN or RGD TIMP-2 expression was not In response to PDGF and/or mechanical TIMP-2 expression by VSMCs on FN, or RGD peptides was and Thus, while mechanical strain suppressed the synthesis of and MMP-1, strain did not regulate TIMP-2 and MMP-2 expression. and TNF-α are potent of MMP-1 expression by VSMCs Z.S. 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Thus, we that small mechanical deformations of VSMCs induce MMP-1 In we that this induction be or biochemical of MMP-1 such as by Surprisingly, we found that small mechanical deformations do not induce MMP-1 but potently suppress MMP-1 synthesis by These that small mechanical deformations may be a on cellular of extracellular matrix degradation. Huhtala et al. (17Huhtala P. Humphries M.J. McCarthy J.B. Tremble P.M. Werb Z. Damsky C.H. J. Cell Biol. 1995; 129: 867-879Crossref PubMed Scopus (369) Google Scholar) and Werb et al. Z. Tremble P.M. E. J. 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Science. 1997; PubMed Scopus Google Scholar). it is that to a cytoskeleton or mechanotransduction to the extracellular by et al. E. Sudhir K. Ives H.E. J. Clin. Invest. 1995; 96: 2364-2372Crossref PubMed Scopus (268) Google Scholar) suggest that may regulate cells are to other fibronectin or studies be to mechanical strain through specific or subunits can regulate MMP One of the of the mechanical strain device used in this is that strains are and highly In other of of the cell culture substrate have very high strains with the strain. example, in one commonly used the strain can from to on the and of the cell (21Schaffer J.L. Rizen M. L'Italien G.J.L. Benbrahim A. Megerman J. Gerstenfeld L.C. Gray M.L. J. Orthop. Res. 1993; 12: 709-719Crossref Scopus (130) Google Scholar). We have previously demonstrated that cellular and fibroblast growth VSMCs are to membrane strains 10% (22Cheng G.C. Briggs W.H. Gerson D.S. Libby P. Grodzinsky A.J. Gray M.L. Lee R.T. Circ. Res. 1997; 80: 28-36Crossref PubMed Scopus (119) Google Scholar). small strains with this cellular deformation device effects as fibroblast growth from strain In the strains in these the that of MMP-1 by strains as small as 1% was to cellular the demonstrating that MMP-2 and TIMP-2 are not suppressed by small strains that the of MMP-1 is These explored some of the of MMP-1 synthesis by strain. in the of PDGF, but suppressed However, are at members of the and other play a et al. J. A. 1997; PubMed Scopus Google Scholar) reported that a of the Ets can suppress MMP-1 In we have not found expression by VSMCs. studies suggest that direct effects of the PDGF are not for the effects of as strain suppress MMP-1 induction by We have these conditions using which demonstrated clear effect of strains on the cytoskeleton not we important as a for mechanotransduction these have mediated synthesis and of PDGF from rat VSMCs to mechanical deformation (7Wilson E. Mai Q. Sudhir K. Weiss R.H. Ives H.E. J. Cell Biol. 1993; 123: 741-747Crossref PubMed Scopus (337) Google Scholar). In we have not observed induction of the or in VSMCs to the small mechanical deformations used in the H. P. and R. is that or in the mechanical strain these mediated of PDGF not small strains can suppress the induction of MMP-1 by In vivo, MMPs are found in repair or such as high locations of the (18Galis Z.S. Sukhova G.K. Lark M.W. Libby P. J. Clin. Invest. 1995; 94: 2493-2503Crossref Scopus (2192) Google Scholar, 19Lee R.T. Schoen F.J. Loree H.M. Lark M.W. Libby P. Arterioscler. Thromb. Vasc. Biol. 1996; 16: 1070-1073Crossref PubMed Scopus (272) Google Scholar, M.J. K. Hembry R. Murphy R. Humphries S. U. S. A. PubMed Scopus Google Scholar). In these cytokines and growth factors are and regulate the repair However, cells in a repairing tissue must a tissue that can withstand mechanical forces on that such as the constant of the or the forces of in the artery. strains of 1% are to the this of cellular deformation was to suppress MMP-1 This the exquisite sensitivity of the cell to mechanical stimuli and the of mechanical forces on to growth mechanotransduction with other systems of