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Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:28-33

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:28-33.)
© 1996 American Heart Association, Inc.


Articles

Regulation of Vascular Smooth Muscle Cell Migration and Proliferation In Vitro and in Injured Rat Arteries by a Synthetic Matrix Metalloproteinase Inhibitor

Nobuya Zempo; Noriyuki Koyama; Richard D. Kenagy; Holly J. Lea; Alexander W. Clowes

From the Department of Surgery, University of Washington, Seattle.

Correspondence to Alexander W. Clowes, MD, Department of Surgery, RF-25, University of Washington, Seattle, WA 98195.

Abstract Smooth muscle cell (SMC) migration and proliferation and extracellular matrix remodeling are essential aspects of the arterial response to injury, vessel development, and atherogenesis. Matrix metalloproteinase (MMP) expression is associated with SMC proliferation and migration after arterial injury. To assess the role of MMPs in SMC proliferation and migration and intimal thickening, we measured the effect of the synthetic MMP inhibitor BB94 (Batimastat) on DNA synthesis and migration of SMCs in vitro as well as the formation of a neointima after balloon injury to the rat carotid artery. BB94 dose-dependently inhibited SMC migration induced by platelet-derived growth factor (PDGF)–BB through a filter coated with a thick basement membrane matrix (Matrigel) layer but did not show any inhibitory effect on SMC migration through a lightly coated filter. At concentrations up to 1 µmol/L, BB94 did not alter DNA synthesis induced by PDGF-AA or PDGF-BB. Treatment with 30 mg BB94·kg-1·d-1 IP for 7 or 14 days after balloon injury to the rat carotid artery decreased the total number of intimal SMC nuclei and suppressed intimal thickening. SMC proliferation (5-bromo-2'-deoxyuridine labeling) was decreased in the media at 2 days, whereas it was increased in the intima at 7 but not 14 days. These results suggest that BB94 inhibits intimal thickening after arterial injury by decreasing SMC migration and proliferation and support the conclusion that MMPs play a significant role in regulating intimal thickening in injured arteries.


Key Words: metalloproteinases • smooth muscle cells • rats • arterial injury • migration




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N. A. Giese, M. M. H. Marijianowski, O. McCook, A. Hancock, V. Ramakrishnan, L. J. Fretto, C. Chen, A. B. Kelly, J. A. Koziol, J. N. Wilcox, et al.
The Role of Alpha and Beta Platelet-Derived Growth Factor Receptor in the Vascular Response to Injury in Nonhuman Primates
Arterioscler Thromb Vasc Biol, April 1, 1999; 19(4): 900 - 909.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
Y. Furukawa, A. Matsumori, N. Ohashi, T. Shioi, K. Ono, A. Harada, K. Matsushima, and S. Sasayama
Anti–Monocyte Chemoattractant Protein-1/Monocyte Chemotactic and Activating Factor Antibody Inhibits Neointimal Hyperplasia in Injured Rat Carotid Arteries
Circ. Res., February 19, 1999; 84(3): 306 - 314.
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Arterioscler. Thromb. Vasc. Bio.Home page
A. Kranzhofer, A. H. Baker, S. J. George, and A. C. Newby
Expression of Tissue Inhibitor of Metalloproteinase-1, -2, and -3 During Neointima Formation in Organ Cultures of Human Saphenous Vein
Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 255 - 265.
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Cardiovasc ResHome page
A. C Newby and A. B Zaltsman
Fibrous cap formation or destruction -- the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation
Cardiovasc Res, February 1, 1999; 41(2): 345 - 360.
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J. Cell Sci.Home page
P. Jones, F. Jones, B Zhou, and M Rabinovitch
Induction of vascular smooth muscle cell tenascin-C gene expression by denatured type I collagen is dependent upon a beta3 integrin-mediated mitogen-activated protein kinase pathway and a 122-base pair promoter element
J. Cell Sci., January 2, 1999; 112(4): 435 - 445.
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Arterioscler. Thromb. Vasc. Bio.Home page
S. Bellosta, D. Via, M. Canavesi, P. Pfister, R. Fumagalli, R. Paoletti, and F. Bernini
HMG-CoA Reductase Inhibitors Reduce MMP-9 Secretion by Macrophages
Arterioscler Thromb Vasc Biol, November 1, 1998; 18(11): 1671 - 1678.
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CirculationHome page
E. J. Topol and P. W. Serruys
Frontiers in Interventional Cardiology
Circulation, October 27, 1998; 98(17): 1802 - 1820.
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Circ. Res.Home page
H. Wang and J. A. Keiser
Vascular Endothelial Growth Factor Upregulates the Expression of Matrix Metalloproteinases in Vascular Smooth Muscle Cells : Role of flt-1
Circ. Res., October 19, 1998; 83(8): 832 - 840.
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Cardiovasc ResHome page
M. Janiszewski, C. A Pasqualucci, L. C Souza, F. Pileggi, P. L da Luz, and F. R M. Laurindo
Oxidized thiols markedly amplify the vascular response to balloon injury in rabbits through a redox active metal-dependent pathway
Cardiovasc Res, August 1, 1998; 39(2): 327 - 338.
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CirculationHome page
H. S. Bassiouny, R. H. Song, X. F. Hong, A. Singh, H. Kocharyan, and S. Glagov
Flow Regulation of 72-kD Collagenase IV (MMP-2) After Experimental Arterial Injury
Circulation, July 14, 1998; 98(2): 157 - 163.
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CirculationHome page
R. D. Kenagy, C. E. Hart, W. G. Stetler-Stevenson, and A. W. Clowes
Primate Smooth Muscle Cell Migration From Aortic Explants Is Mediated by Endogenous Platelet-Derived Growth Factor and Basic Fibroblast Growth Factor Acting Through Matrix Metalloproteinases 2 and 9
Circulation, November 18, 1997; 96(10): 3555 - 3560.
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Arterioscler. Thromb. Vasc. Bio.Home page
S. J. George, J. L. Johnson, G. D. Angelini, and J. Y. Jeremy
Short-term Exposure to Thapsigargin Inhibits Neointima Formation in Human Saphenous Vein
Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 2500 - 2506.
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Circ. Res.Home page
J. G. Pickering, S. Uniyal, C. M. Ford, T. Chau, M. A. Laurin, L. H. Chow, C. G. Ellis, J. Fish, and B. M. C. Chan
Fibroblast Growth Factor-2 Potentiates Vascular Smooth Muscle Cell Migration to Platelet-Derived Growth Factor : Upregulation of {alpha}2ß1 Integrin and Disassembly of Actin Filaments
Circ. Res., May 19, 1997; 80(5): 627 - 637.
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Cardiovasc ResHome page
A. Hultgardh-Nilsson, C. Lovdahl, K. Blomgren, Bengt Kallin, and J. Thyberg
Expression of phenotype- and proliferation-related genes in rat aortic smooth muscle cells in primary culture
Cardiovasc Res, May 1, 1997; 34(2): 418 - 430.
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CirculationHome page
P. R. Moreno, V. H. Bernardi, J. Lopez-Cuellar, J. B. Newell, C. McMellon, H. K. Gold, I. F. Palacios, V. Fuster, and J. T. Fallon
Macrophage Infiltration Predicts Restenosis After Coronary Intervention in Patients With Unstable Angina
Circulation, December 15, 1996; 94(12): 3098 - 3102.
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Arterioscler. Thromb. Vasc. Bio.Home page
R.D. Kenagy, S. Vergel, E. Mattsson, M. Bendeck, M.A. Reidy, and A.W. Clowes
The Role of Plasminogen, Plasminogen Activators, and Matrix Metalloproteinases in Primate Arterial Smooth Muscle Cell Migration
Arterioscler Thromb Vasc Biol, November 1, 1996; 16(11): 1373 - 1382.
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Circ. Res.Home page
R. Forough, N. Koyama, D. Hasenstab, H. Lea, M. Clowes, S. T. Nikkari, and A. W. Clowes
Overexpression of Tissue Inhibitor of Matrix Metalloproteinase-1 Inhibits Vascular Smooth Muscle Cell Functions In Vitro and In Vivo
Circ. Res., October 1, 1996; 79(4): 812 - 820.
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J. Biol. Chem.Home page
S. Eguchi, P. J. Dempsey, G. D. Frank, E. D. Motley, and T. Inagami
Activation of MAPKs by Angiotensin II in Vascular Smooth Muscle Cells. METALLOPROTEASE-DEPENDENT EGF RECEPTOR ACTIVATION IS REQUIRED FOR ACTIVATION OF ERK AND p38 MAPK BUT NOT FOR JNK
J. Biol. Chem., March 9, 2001; 276(11): 7957 - 7962.
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Am. J. Physiol. Cell Physiol.Home page
C. Chassagne, C. Adamy, P. Ratajczak, B. Gingras, E. Teiger, E. Planus, P. Oliviero, L. Rappaport, J.-L. Samuel, and S. Meloche
Angiotensin II AT2 receptor inhibits smooth muscle cell migration via fibronectin cell production and binding
Am J Physiol Cell Physiol, April 1, 2002; 282(4): C654 - C664.
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Circ. Res.Home page
J.-S. Silvestre, Z. Mallat, R. Tamarat, M. Duriez, A. Tedgui, and B. I. Levy
Regulation of Matrix Metalloproteinase Activity in Ischemic Tissue by Interleukin-10: Role in Ischemia-Induced Angiogenesis
Circ. Res., August 3, 2001; 89(3): 259 - 264.
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