Plasminogen activator inhibitor type 1 enhances neointima formation after oxidative vascular injury in atherosclerosis-prone mice.
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.


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-beta activation and apoptosis.
Zhu
Y
Y
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, USA.
Farrehi
P M
PM
Fay
W P
WP
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000473:pathology* / Q000503:physiopathology; D020212:Carotid Artery Injuries / Q000139:chemically induced; D017536:Carotid Artery, Common / Q000187:drug effects / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002712:Chlorides; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D005260:Female; D005290:Ferric Compounds / Q000008:administration & dosage; D005838:Genotype; D006965:Hyperplasia; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013927:Thrombosis / Q000473:pathology; D017539:Tunica Intima / Q000473:pathology*
D001057:Apolipoproteins E; D002712:Chlorides; D002791:Cholesterol, Dietary; D005290:Ferric Compounds; D017395:Plasminogen Activator Inhibitor 1; C024555:ferric chloride