Abstract
Tissue engineering offers the opportunity to develop vascular substitutes that mimic the responsive nature of native arteries. A good blood vessel substitute should be able to remodel its matrix in response to mechanical stimulation, as imposed by the hemodynamic environment. We have developed a novel method of studying the influence of mechanical strain on the remodeling of cell-seeded collagen gel blood vessel analogs. We assessed the remodeling capacity by examining the effect of mechanical conditioning upon the expression of enzymes which remodel the extracellular matrix, called matrix metalloproteinases (MMPs), and upon the mechanical properties of the constructs. We found that subjecting collagen constructs to a 10% cyclic radial distention, over a course of 4 days, resulted in an overall increase in the production of MMP-2. Cyclic mechanical strain also stimulated enzymatic activation of latent MMP-2. We found that cyclic strain also significantly increased the mechanical strength and material modulus, as indicated by an increase in circumferential tensile properties of the constructs. These observations suggested that MMP-2-dependent remodeling affects the material properties of vascular tissue analogs. To further investigate this possible connection we examined the effects of dynamic conditioning in the presence of two nonspecific inhibitors of MMP activity. Interestingly, we found that nonspecific inhibition of MMP ablated the benefits of mechanical conditioning upon mechanical properties. Our observations suggest that a better understanding of the complex relation between mechanical stimulation and construct remodeling is key for the proper design of tissue-engineered blood vessel substitutes. © 2001 Biomedical Engineering Society.
PAC01: 8719Rr, 8714Ee, 8717-d
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Bullard, K. M., J. Mudgett, H. Scheuenstuhl, T. K. Hunt, and M. J. Banda. Stromelysin-1–deficient fibroblasts display impaired contraction in vitro. J. Surg. Res.84:31–34, 1999.
Galis, Z., K. Asanuma, D. Godin, and X. Meng. N-acetyl-cysteine decreases the matrix-degrading capacity of macrophage-derived foam cells: New target for antioxidant therapy?Circulation97:2445–2454, 1998.
Galis, Z. S.. Metalloproteinases in remodeling of vascular extracellular matrix. Fibrinol. Proteol.13:54–63, 1999.
Galis, Z. S., M. Muszynski, G. K. Sukhova, E. Simon-Morrissey, E. N. Uenmori, M. W. Lark, E. Amento, and P. Libby. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ. Res.75:181–189, 1994.
Galis, Z. S., G. K. Sukhova, M. W. Lark, and P. Libby. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Invest.94:2493–2503, 1994.
Girton, T. S., T. R. Oegema, and R. T. Tranquillo. Exploiting glycation to stiffen and strengthen tissue equivalents for tissue engineering. J. Biomed. Mater. Res.46:87–92, 1999.
Haas, T. L., S. J. Davis, and J. A. Madri. Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1–MMP and MMP-2 in microvascular endothelial cells. J. Biol. Chem.273:3604–3610, 1998.
Howard, A. B., R. W. Alexander, R. M. Nerem, K. K. Griendling, and W. R. Taylor. Cyclic strain induces an oxidative stress in endothelial cells. Am. J. Physiol.272:C421–427, 1997.
James, T. W., R. Wagner, L. A. White, R. M. Zwolak, and C. E. Brinckerhoff. Induction of collagenase and stromelysin gene expression by mechanical injury in a vascular smooth muscle-derived cell line. J. Cell Physiol.157:426–437, 1993.
Kanda, K., and T. Matsuda. Mechanical stress-induced orientation and ultrastructural change of smooth muscle cells cultured in three-dimensional collagen lattices. Cell Transplant3:481–492, 1994.
Khaw, P. T., and G. S. Schultz. U.S. Patent No. PCT/GB95/00576, 1995.
Kim, B. S., J. Nikolovski, J. Bonadio, and D. J. Mooney. Cyclic mechanical strain regulates the development of engineered smooth muscle tissue. Nat. Biotechnol.17:979–983, 1999.
Lee, R. T., F. Berditchevski, G. C. Cheng, and M. E. Hemler. Integrin-mediated collagen matrix reorganization by cultured human vascular smooth muscle cells. Circ. Res.76:209–214, 1995.
Murphy, G., F. Willenbrock, T. Crabbe, M. O'shea, R. Ward, S. Atkinson, J. O'Connell, and A. Docherty. Regulation of matrix metalloproteinase activity. Ann. N.Y. Acad. Sci.732:31–41, 1994.
Myers, S. A., and R. G. Wolowacz. Tetracycline-based MMP inhibitors can prevent fibroblast-mediated collagen gel contraction in vitro. Adv. Dental Res.12:86–93, 1998.
Nagase, H., J. J. Enghild, K. Suzuki, and G. Salvesen. Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4–aminophenyl)mercuric acetate. Biochemistry29:5783–5789, 1990.
Niklason, L. E., J. Gao, W. M. Abbott, K. K. Hirschi, S. Houser, R. Marini, and R. Langer. Functional arteries grown in vitro [see comments]. Science284:489–493, 1999.
Rajagopalan, S., X. P. Meng, S. Ramasamy, D. G. Harrison, and Z. S. Galis. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J. Clin. Invest.98:2572–2579, 1996.
Seliktar, D., R. A. Black, R. P. Vito, and R. M. Nerem. Dynamic mechanical conditioning of collagen-gel blood vessel constructs induces remodeling in vitro. Ann. Biomed. Eng.28:351–362, 2000.
Vorp, D. A., D. G. Peters, and M. W. Webster. Gene expression is altered in perfused arterial segments exposed to cyclic flexure ex vivo. Ann. Biomed. Eng.27:366–371, 1999.
Yang, J. H., W. H. Briggs, P. Libby, and R. T. Lee. Small mechanical strains selectively suppress matrix metalloproteinase-1 expression by human vascular smooth muscle cells. J. Biol. Chem.273:6550–6555, 1998.
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Seliktar, D., Nerem, R.M. & Galis, Z.S. The Role of Matrix Metalloproteinase-2 in the Remodeling of Cell-Seeded Vascular Constructs Subjected to Cyclic Strain. Annals of Biomedical Engineering 29, 923–934 (2001). https://doi.org/10.1114/1.1415522
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DOI: https://doi.org/10.1114/1.1415522