Published online before print May 29, 2003, doi: 10.1161/01.RES.0000079027.44309.53
© 2003 American Heart Association, Inc.
Cellular Biology |
Dismantling of Cadherin-Mediated Cell-Cell Contacts Modulates Smooth Muscle Cell Proliferation
From the Bristol Heart Institute, Level 7, Bristol Royal Infirmary, Bristol, UK.
Correspondence to Dr Sarah Jane George, Bristol Heart Institute, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, UK. E-mail s.j.george{at}bris.ac.uk
Proliferation of vascular smooth muscle cells (VSMCs) contributes to intimal thickening during atherosclerosis and restenosis. The cadherins are transmembrane proteins, which form cell-cell contacts and may regulate VSMC proliferation. In this study, N-cadherin protein concentration was significantly reduced by stimulation of proliferation with fetal calf serum (FCS) and platelet-derived growth factor-BB (PDGF-BB) in human saphenous vein VSMCs. Furthermore, overexpression of a truncated N-cadherin, which acts as a dominant-negative increased VSMC proliferation. The amount of an extracellular fragment of N-cadherin (
90 kDa) in the media after 24 hours was increased by 12-fold by FCS and 11-fold by PDGF-BB, suggesting that N-cadherin levels are regulated by proteolytic shedding. Incubation with a synthetic metalloproteinase inhibitor or adenoviral overexpression of the endogenous tissue inhibitors of metalloproteinases (TIMPs) demonstrated that metalloproteinase activity was responsible in part for this proteolysis. Although total levels of ß-catenin protein were not affected, ß-catenin was translocated to the nucleus after stimulation with FCS and PDGF-BB. Our data indicates cadherin-mediated cell-cell contacts modulate proliferation in VSMCs. Furthermore, disruption of N-cadherin cell-cell contacts mediated in part by metalloproteinase activity occurs during VSMC proliferation, releasing ß-catenin and possibly inducing ß-catenin-mediated intracellular signaling.
Key Words: smooth muscle • proliferation • cadherin • metalloproteinase
This article has been cited by other articles:
 |
|
 |
|
  C. A. Lyon, J. L. Johnson, H. Williams, G. B. Sala-Newby, and S. J. George Soluble N-Cadherin Overexpression Reduces Features of Atherosclerotic Plaque Instability Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 195 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Dwivedi, S. C. Slater, and S. J. George MMP-9 and -12 cause N-cadherin shedding and thereby {beta}-catenin signalling and vascular smooth muscle cell proliferation Cardiovasc Res, January 1, 2009; 81(1): 178 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. O. Nunes, M. Schmidt, G. Dueck, H. Baarsma, A. J. Halayko, H. A. M. Kerstjens, H. Meurs, and R. Gosens GSK-3/{beta}-catenin signaling axis in airway smooth muscle: role in mitogenic signaling Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1110 - L1118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-L. Niu, J. Li, Z. S. Hakim, M. Rojas, M. S. Runge, and N. R. Madamanchi Leukocyte Antigen-related Deficiency Enhances Insulin-like Growth Factor-1 Signaling in Vascular Smooth Muscle Cells and Promotes Neointima Formation in Response to Vascular Injury J. Biol. Chem., July 6, 2007; 282(27): 19808 - 19819. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Couffinhal, P. Dufourcq, and C. Duplaa {beta}-Catenin Nuclear Activation: Common Pathway Between Wnt and Growth Factor Signaling in Vascular Smooth Muscle Cell Proliferation? Circ. Res., December 8, 2006; 99(12): 1287 - 1289. [Full Text] [PDF]
|
|
|
|
|
|
H. Quasnichka, S. C. Slater, C. A. Beeching, M. Boehm, G. B. Sala-Newby, and S. J. George Regulation of Smooth Muscle Cell Proliferation by {beta}-Catenin/T-Cell Factor Signaling Involves Modulation of Cyclin D1 and p21 Expression Circ. Res., December 8, 2006; 99(12): 1329 - 1337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Wu, M. Bond, G. B. Sala-Newby, and A. C. Newby Altered S-Phase Kinase-Associated Protein-2 Levels Are a Major Mediator of Cyclic Nucleotide-Induced Inhibition of Vascular Smooth Muscle Cell Proliferation Circ. Res., May 12, 2006; 98(9): 1141 - 1150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Hou, L. Liu, S. Anees, S. Hiroyasu, and N. E.S. Sibinga The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals J. Cell Biol., May 8, 2006; 173(3): 417 - 429. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Franco, B. Ho, D. Mulholland, G. Hou, M. Islam, K. Donaldson, and M. P. Bendeck Doxycycline Alters Vascular Smooth Muscle Cell Adhesion, Migration, and Reorganization of Fibrillar Collagen Matrices Am. J. Pathol., May 1, 2006; 168(5): 1697 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Newby Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates Cardiovasc Res, February 15, 2006; 69(3): 614 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Covington, R. C. Burghardt, and A. R. Parrish Ischemia-induced cleavage of cadherins in NRK cells requires MT1-MMP (MMP-14) Am J Physiol Renal Physiol, January 1, 2006; 290(1): F43 - F51. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Covington, K. J. Bayless, R. C. Burghardt, G. E. Davis, and A. R. Parrish Ischemia-induced cleavage of cadherins in NRK cells: evidence for a role of metalloproteinases Am J Physiol Renal Physiol, August 1, 2005; 289(2): F280 - F288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Koutsouki, C. A. Beeching, S. C. Slater, O. W. Blaschuk, G. B. Sala-Newby, and S. J. George N-Cadherin-Dependent Cell-Cell Contacts Promote Human Saphenous Vein Smooth Muscle Cell Survival Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 982 - 988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Newby Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture Physiol Rev, January 1, 2005; 85(1): 1 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Ivanov, M. Philippova, R. Allenspach, P. Erne, and T. Resink T-cadherin upregulation correlates with cell-cycle progression and promotes proliferation of vascular cells Cardiovasc Res, October 1, 2004; 64(1): 132 - 143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Slater, E. Koutsouki, C. L. Jackson, R. C. Bush, G. D. Angelini, A. C. Newby, and S. J. George R-Cadherin:{beta}-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1204 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Blindt, A.-K. Bosserhoff, J. Dammers, N. Krott, L. Demircan, R. Hoffmann, P. Hanrath, C. Weber, and F. Vogt Downregulation of N-cadherin in the neointima stimulates migration of smooth muscle cells by RhoA deactivation Cardiovasc Res, April 1, 2004; 62(1): 212 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Johnson and Z. S. Galis Matrix Metalloproteinase-2 and -9 Differentially Regulate Smooth Muscle Cell Migration and Cell-Mediated Collagen Organization Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 54 - 60. [Abstract] [Full Text] [PDF]
|
|