(Circulation. 2001;103:3105.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Plasminogen Activator Inhibitor Type 1 Enhances Neointima Formation After Oxidative Vascular Injury in Atherosclerosis-Prone Mice
From the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.
Correspondence to William P. Fay, MD, University of Michigan Medical Center, 7301 MSRB III, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0644. E-mail wfay{at}umich.edu
Background—Plasminogen activator inhibitor type 1 (PAI-1) inhibits neointima formation after vascular injury. Hyperlipidemia modulates the expression of multiple genes, however, and the effects of PAI-1 on the arterial response to injury under hyperlipidemic conditions are unknown. The purpose of this study was to examine the impact of PAI-1 on intimal hyperplasia and other vascular changes that develop after arterial injury in apolipoprotein E–deficient (apoE-/-) mice.
Methods and Results—Ferric chloride injury of the midportion of the common carotid arteries of apoE-/- mice (n=22) induced formation of a neointima that contained smooth muscle cells, foam cells, neutral lipid, tissue factor, and von Willebrand factor. Interactions between vascular injury and apolipoprotein E deficiency were strongly synergistic; either stimulus alone was insufficient to induce significant neointima formation. Mean intima/media ratios were significantly greater (P<0.03) in apoE-/-, PAI-1+/+ mice (5.6±1.8, n=12) than in apoE-/-, PAI-1-/- mice (1.2±0.55, n=12), as were the percentages of bromodeoxyuridine-positive cells in the intima and media (P<0.03). Transiently occlusive (<48 hours) and nonocclusive mural thrombi persisted longer in apoE-/-, PAI-1+/+ mice than in apoE-/-, PAI-1-/- mice.
Conclusions—In atherosclerosis-prone mice, PAI-1 promotes neointima formation after oxidative vascular injury. The apparent hyperlipidemia-dependent effect of PAI-1 may be mediated by its capacity to inhibit the clearance of platelet-fibrin thrombi that can deliver growth factors to the blood vessel wall or be incorporated into developing vascular lesions. Alternatively, hyperlipidemia may alter the pattern of gene expression in the blood vessel wall to enhance potential effects of PAI-1 on antiproliferative processes, such as transforming growth factor-ß activation and apoptosis.
Key Words: plasminogen activators • apolipoproteins • vascular biology
This article has been cited by other articles:
 |
|
 |
|
  J. Wu, L. Peng, G. A. McMahon, D. A. Lawrence, and W. P. Fay Recombinant Plasminogen Activator Inhibitor-1 Inhibits Intimal Hyperplasia Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1565 - 1570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Drinane, J. Mollmark, L. Zagorchev, K. Moodie, B. Sun, A. Hall, S. Shipman, P. Morganelli, M. Simons, and M. J. Mulligan-Kehoe The Antiangiogenic Activity of rPAI-123 Inhibits Vasa Vasorum and Growth of Atherosclerotic Plaque Circ. Res., February 13, 2009; 104(3): 337 - 345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L.C. Hoo, W.S. Chow, M.H. Yau, A. Xu, A. W.K. Tso, H.F. Tse, C. H.Y. Fong, S. Tam, L. Chan, and K. S.L. Lam Adiponectin Mediates the Suppressive Effect of Rosiglitazone on Plasminogen Activator Inhibitor-1 Production Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2777 - 2782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. P. Fay, N. Garg, and M. Sunkar Vascular Functions of the Plasminogen Activation System Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1231 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yokoi, K. Fukuo, O. Yasuda, M. Hotta, J. Miyazaki, Y. Takemura, H. Kawamoto, H. Ichijo, and T. Ogihara Apoptosis Signal-Regulating Kinase 1 Mediates Cellular Senescence Induced by High Glucose in Endothelial Cells Diabetes, June 1, 2006; 55(6): 1660 - 1665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Schafer, M. R. Schroeter, C. Dellas, M. Puls, M. Nitsche, E. Weiss, G. Hasenfuss, and S. V. Konstantinides Plasminogen Activator Inhibitor-1 From Bone Marrow-Derived Cells Suppresses Neointimal Formation After Vascular Injury in Mice Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1254 - 1259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Otsuka, R. Agah, A. D. Frutkin, T. N. Wight, and D. A. Dichek Transforming Growth Factor Beta 1 Induces Neointima Formation Through Plasminogen Activator Inhibitor-1-Dependent Pathways Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 737 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Shi, H. Pei, J. J. Fischer, J. C. James, J. F. Angle, A. H. Matsumoto, G. A. Helm, and I. J. Sarembock Neointimal formation in two apolipoprotein E-deficient mouse strains with different atherosclerosis susceptibility J. Lipid Res., November 1, 2004; 45(11): 2008 - 2014. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Schneider, M. Hayes, M. Wadsworth, H. Taatjes, M. Rincon, D. J. Taatjes, and B. E. Sobel Attenuation of Neointimal Vascular Smooth Muscle Cellularity in Atheroma by Plasminogen Activator Inhibitor Type 1 (PAI-1) J. Histochem. Cytochem., August 1, 2004; 52(8): 1091 - 1099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Kerlin, B. C. Cooley, B. H. Isermann, I. Hernandez, R. Sood, M. Zogg, S. B. Hendrickson, M. W. Mosesson, S. Lord, and H. Weiler Cause-effect relation between hyperfibrinogenemia and vascular disease Blood, March 1, 2004; 103(5): 1728 - 1734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pynn, K. Schafer, S. Konstantinides, and M. Halle Exercise Training Reduces Neointimal Growth and Stabilizes Vascular Lesions Developing After Injury in Apolipoprotein E-Deficient Mice Circulation, January 27, 2004; 109(3): 386 - 392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Schafer, M. Halle, C. Goeschen, C. Dellas, M. Pynn, D. J. Loskutoff, and S. Konstantinides Leptin Promotes Vascular Remodeling and Neointimal Growth in Mice Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 112 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Uchida, T. Inoue, H. Kamishirado, K. Takayanagi, and S. Morooka Prediction of Short-Term Progression or Regression of Atherosclerotic Coronary Artery Disease by Lipoprotein (a): A Quantitative Coronary Angiographic Study Angiology, November 1, 2003; 54(6): 641 - 646. [Abstract] [PDF]
|
|
|
|
|
|
B. E. Sobel, D. J. Taatjes, and D. J. Schneider Intramural Plasminogen Activator Inhibitor Type-1 and Coronary Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 1979 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Schafer, K. Muller, A. Hecke, E. Mounier, J. Goebel, D. J. Loskutoff, and S. Konstantinides Enhanced Thrombosis in Atherosclerosis-Prone Mice Is Associated With Increased Arterial Expression of Plasminogen Activator Inhibitor-1 Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 2097 - 2103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Bot, J. H. von der Thusen, M. M.P.C. Donners, A. Lucas, M. L. Fekkes, S. C.A. de Jager, J. Kuiper, M. J.A.P. Daemen, T. J.C. van Berkel, S. Heeneman, et al. Serine Protease Inhibitor Serp-1 Strongly Impairs Atherosclerotic Lesion Formation and Induces a Stable Plaque Phenotype in ApoE-/- Mice Circ. Res., September 5, 2003; 93(5): 464 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Konstantinides, K. Schafer, and D. J. Loskutoff Do PAI-1 and Vitronectin Promote or Inhibit Neointima Formation?: The Exact Role of the Fibrinolytic System in Vascular Remodeling Remains Uncertain Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1943 - 1945. [Full Text] [PDF]
|
|
|
|
|
|
V. de Waard, E. K. Arkenbout, P. Carmeliet, V. Lindner, and H. Pannekoek Plasminogen Activator Inhibitor 1 and Vitronectin Protect Against Stenosis in a Murine Carotid Artery Ligation Model Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1978 - 1983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tanaka, H. Koyama, T. Ichii, A. Shioi, M. Hosoi, E. W. Raines, and Y. Nishizawa Fibrillar Collagen Regulation of Plasminogen Activator Inhibitor-1 Is Involved in Altered Smooth Muscle Cell Migration Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1573 - 1578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Schafer, S. Konstantinides, C. Riedel, T. Thinnes, K. Muller, C. Dellas, G. Hasenfuss, and D. J. Loskutoff Different Mechanisms of Increased Luminal Stenosis After Arterial Injury in Mice Deficient for Urokinase- or Tissue-Type Plasminogen Activator Circulation, October 1, 2002; 106(14): 1847 - 1852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Peng, N. Bhatia, A. C. Parker, Y. Zhu, and W. P. Fay Endogenous Vitronectin and Plasminogen Activator Inhibitor-1 Promote Neointima Formation in Murine Carotid Arteries Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 934 - 939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Luttun, F. Lupu, E. Storkebaum, M. F. Hoylaerts, L. Moons, J. Crawley, F. Bono, A. R. Poole, P. Tipping, J.-M. Herbert, et al. Lack of Plasminogen Activator Inhibitor-1 Promotes Growth and Abnormal Matrix Remodeling of Advanced Atherosclerotic Plaques in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 499 - 505. [Abstract] [Full Text] [PDF]
|
|