(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
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