Local plasminogen activator inhibitor type 1 overexpression in rat carotid artery enhances thrombosis and endothelial regeneration while inhibiting intimal thickening.
Elevated levels of plasminogen activator inhibitor type 1 (PAI-1) are found in advanced atherosclerotic plaque compared with normal vessel and may contribute to plaque progression and complications associated with plaque rupture. Increased expression of PAI-1 probably contributes to the thrombotic properties of advanced atherosclerotic plaque by impeding plasmin generation and degradation of fibrin. To test this hypothesis, we have deliberately created synthetic neointimas by seeding onto the denuded luminal surface of rat carotid arteries smooth muscle cells transduced with replication-defective retrovirus encoding rat PAI-1. This cell-based gene transfer method results in stable, long-term, and localized gene expression. PAI-1 overexpression increases mural thrombus accumulation at 4 days but decreases neointimal area by 30% and 25% at 1 week and 2 weeks, respectively. PAI-1 overexpression accelerates reendothelialization of injured arteries compared with control arteries at 1 week, 2 weeks, and 1 month. PAI-1 overexpression does not alter matrix accumulation at 1 week. Increased PAI-1 expression in the rat carotid artery enhances thrombosis and endothelial regeneration while inhibiting intimal thickening. These results suggest that PAI-1 could play a direct role in the development of advanced atherosclerotic plaque and in the repair of the diseased vessel after fibrous cap disruption.
Hasenstab
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Department of Surgery, University of Washington, School of Medicine, Seattle 98195-6410, USA.
Lea
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Clowes
A W
AW
D000818:Animals; D015152:Blotting, Northern; D002339:Carotid Arteries / Q000737:chemistry / Q000473:pathology*; D020212:Carotid Artery Injuries / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D005342:Fibrinolysis / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D005822:Genetic Vectors; D008855:Microscopy, Electron, Scanning; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D013927:Thrombosis / Q000503:physiopathology*; D017539:Tunica Intima / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger