Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene

Erickson, Laurence A.; Fici, Gregory J.; Lund, John E.; Boyle, T P; Polites, H. Greg; Marotti, Keith R.

doi:10.1038/346074a0

Cited by 261 publications

(100 citation statements)

References 14 publications

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“…6 On the one hand, local PAI-1 overexpression should enhance fibrin accumulation and thereby contribute to the growth of atherosclerotic lesions. 3,7 On the other hand, increased PAI-1 inhibits smooth muscle cell (SMC) migration and the formation of neointima in injured mouse vessels; this result supports the hypothesis that PAI-1 overexpression retards the growth of atherosclerotic lesions. 8,9 In the following experiments, we have attempted to define the role of PAI-1 in the intima to resolve this dilemma and to understand how PAI-1 may influence the biology of the advanced atherosclerotic lesion.…”

supporting

confidence: 59%

Local Plasminogen Activator Inhibitor Type 1 Overexpression in Rat Carotid Artery Enhances Thrombosis and Endothelial Regeneration While Inhibiting Intimal Thickening

Hasenstab

Lea

Clowes

2000

ATVB

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Abstract-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. Key Words: plasminogen activator inhibitor type 1 Ⅲ carotid arteries Ⅲ thrombosis Ⅲ fibrinolysis Ⅲ endothelium P lasminogen activator inhibitor type 1 (PAI-1) is the primary physiological inhibitor of the plasminogen activator system and thereby blocks the conversion of plasminogen to plasmin. The plasminogen activator (PA) system is composed of urokinase PA (uPA) and tissue PA that proteolytically convert plasminogen to the serine protease plasmin. Components of the PA system are localized to the cell surface by receptors or extracellular matrix binding sites.Increased expression of PAI-1 has been demonstrated in atherosclerotic arteries. 1,2 PAI-1 is elevated in mesenchymalappearing intimal cells at the base of the plaque and in the necrotic core. Its function in the advanced atherosclerotic lesion is not known. PAI-1 may limit the fibrinolytic capacity of the plaque. 3 It also might modulate cellular proliferation or migration in the lesion through changes in matrix composition and growth factor release. The effects of PAI-1 are likely to be exerted locally in view of the fact that a majority of patients with generalized atherosclerosis have normal plasma fibrinolytic profiles. 4,5 The various biological effects of PAI-1 generate a dilemma. 6 On the one hand, local PAI-1 overexpression should enhance fibrin accumulation and thereby contribute to the growth of atherosclerotic lesions. 3,7 On the other hand, increased PAI-1 inhibits smooth muscle cell (SMC) migration and the formation of neointima in injured mouse vessels; this result supports the hypothesis that PAI-1 overexpression retards the growth of atherosclerot...

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supporting

confidence: 59%

Local Plasminogen Activator Inhibitor Type 1 Overexpression in Rat Carotid Artery Enhances Thrombosis and Endothelial Regeneration While Inhibiting Intimal Thickening

Hasenstab

Lea

Clowes

2000

ATVB

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“…PAI-1 knockout mice are less likely to develop venous thrombi, 21 whereas mice overexpressing a human transgene develop spontaneous thromboses. 22 Our results suggest that radiationinduced hypofibrinolysis is abolished in PAI-1 Ϫ/Ϫ mice and consequently protects these mice against the deleterious effects of the loss of thromboresistance of the endothelium.…”

Section: Discussionmentioning

confidence: 57%

Essential Role of Plasminogen Activator Inhibitor Type-1 in Radiation Enteropathy

Milliat

Sabourin

Tarlet

et al. 2008

The American Journal of Pathology

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Intestinal radiation injury is a dose-limiting factor in radiation therapy for abdominal and pelvic cancers. Because transforming growth factor-␤1 is a key mediator involved in radiation-induced damage, we hypothesized that its target gene, plasminogen activator inhibitor type 1 (PAI-1), is an essential mediator of intestinal radiation toxicity. In a model of radiation enteropathy, survival was monitored and intestinal radiation injury was assessed in both wild-type (Wt) and PAI-1 knockout mice. Immunohistochemical labeling of PAI-1 was also assessed in patients treated with preoperative radiotherapy for rectal adenocarcinoma. Finally, the molecular mechanisms involved in radiation-induced PAI-1 expression were investigated. We found that PAI-1 ؊/؊ mice exhibited increased survival and better intestinal function compared with Wt mice. Intestinal radiation injury was attenuated in irradiated PAI-1 ؊/؊ mice compared with irradiated Wt mice, and irradiation increased blood cell-endothelial cell interactions in Wt but not PAI-1 ؊/؊ mice. In vivo, radiation-induced intestinal damage in mice, as well as in patients treated with radiotherapy, was associated with the up-regulation of PAI-1 in the endothelium. In vitro, irradiation increased PAI-1 expression in endothelial cells by a p53/Smad3-dependent mechanism. Together, these data demonstrate that PAI-1 plays a critical role in radiation-induced intestinal damage, suggesting that PAI-1 is an attractive target for preventing or reducing the side effects of radiation therapy.

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“…3 Inhibition of plasminogen activation by PAI-1 impairs fibrinolysis and thereby promotes thrombosis. 4,5 In addition, PAI-1 has been shown to regulate ECM turnover and vascular smooth muscle cell (VSMC) migration, 6,7 2 key processes in vascular remodeling and atherogenesis.…”

mentioning

confidence: 99%

Natriuretic Factors and Nitric Oxide Suppress Plasminogen Activator Inhibitor-1 Expression in Vascular Smooth Muscle Cells

Bouchie

Hansen

Feener

1998

ATVB

105

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Abstract-Increased expression of plasminogen activator inhibitor-1 (PAI-1) has been reported in atherosclerotic and balloon-injured vessels. Little is known regarding the factors and mechanisms that may negatively regulate PAI-1 expression. In this report, the effect of cGMP-coupled vasoactive hormones, including natriuretic factors and nitric oxide, on the regulation of PAI-1 expression in vascular smooth muscle cells was examined. Atrial natriuretic factor 1-28 (ANF) and C-type natriuretic factor-22 (CNP) reduced angiotensin II (Ang II)-and platelet-derived growth factor-stimulated PAI-1 mRNA expression in rat aortic smooth muscle cells by 50% to 70%, with corresponding reductions in PAI-1 protein release. Treatment of human aortic smooth muscle cells with CNP similarly inhibited both platelet-derived growth factor-induced PAI-1 mRNA expression and PAI-1 protein release by 50%. Dose-response studies revealed that the inhibitory effects of CNP and ANF on PAI-1 expression were concentration dependent, with IC 50 s of Ϸ1 nmol/L for both natriuretic peptides. Ang II-stimulated PAI-1 expression was also inhibited by the nitric oxide donor S-nitroso-N-acetylpenicillamine.

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Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene

Cited by 261 publications

References 14 publications

Local Plasminogen Activator Inhibitor Type 1 Overexpression in Rat Carotid Artery Enhances Thrombosis and Endothelial Regeneration While Inhibiting Intimal Thickening

Local Plasminogen Activator Inhibitor Type 1 Overexpression in Rat Carotid Artery Enhances Thrombosis and Endothelial Regeneration While Inhibiting Intimal Thickening

Essential Role of Plasminogen Activator Inhibitor Type-1 in Radiation Enteropathy

Natriuretic Factors and Nitric Oxide Suppress Plasminogen Activator Inhibitor-1 Expression in Vascular Smooth Muscle Cells

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