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 neointim a formation after vascular injury. Hyperlipidemia modulates the expression of multiple genes, however, and the effects of PAI-I on the arterial respon se to injury under hyperlipidemic conditions are unknown. The purpose of th is study was to examine the impact of PAI-I on intimal hyperplasia and othe r vascular changes that develop after arterial injury in apolipoprotein E-d eficient (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 facto r, and von Willebrand factor. Interactions between vascular injury and apol ipoprotein E deficiency were strongly synergistic; either stimulus alone wa s insufficient to induce significant neointima formation. Mean intima/media ratios were significantly greater (P<0.03) in apoE(-/-), PAI-1(+/+) mice ( 5.6<plus/minus>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 i ntima and media (P<0.03). Transiently occlusive (<48 hours) and nonocclusiv e mural thrombi persisted longer in apoE(-/-), PAI-1(+/+) mice than in apoE (-/-), PAI-1(-/-) mice. Conclusions-In atherosclerosis-prone mice, PAI-1 promotes neointima formati on after oxidative vascular injury. The apparent hyperlipidemia-dependent e ffect 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, h yperlipidemia 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.