Ambient oxygen tension modulates endothelial fibrinolysis

Gertler, Jonathan P.; Perry, Leland; L’Italien, Gilbert; Chung‐Welch, Nancy; Cambria, Richard P.; Orkin, Roslyn W.; Abbott, William M.

doi:10.1016/0741-5214(93)90548-z

Cited by 68 publications

(40 citation statements)

References 13 publications

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“…Although tPA mRNA is reportedly unchanged after endothelial exposure to anoxia (9) or hypoxia (10), the PAI-1/ tPA antigen ratio appears to be increased (10), which may contribute to the apparent hypofibrinolytic state of endothelial cells exposed to hypoxia in vitro (10). Because no similar data are available for macrophages, and our in vivo experiments suggested macrophages to be the major source of PAI-1 in (Left) PAI-1 antigen.…”

Section: Resultsmentioning

confidence: 55%

“…Human umbilical vein cells exposed to anoxic conditions demonstrate no change in levels of tissue-type plasminogen activator (tPA) or plasminogen activator inhibitor-1 (PAI-1) (9), although reoxygenation was associated with decreased mRNA and activity of both related to the duration of antecedent hypoxic exposure. In contrast, other studies have shown that PAI-1 mRNA is increased in endothelial cells (with an inhibition of fibrinolysis) after 24 h of exposure to an ambient oxygen concentration of 40 Torr (10).…”

Section: Introductionmentioning

confidence: 62%

See 1 more Smart Citation

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Pinsky¹,

Liao²,

Lawson³

et al. 1998

J. Clin. Invest.

182

109

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Oxygen deprivation, as occurs during tissue ischemia, tips the natural anticoagulant/procoagulant balance of the endovascular wall to favor activation of coagulation. To investigate the effects of low ambient oxygen tension on the fibrinolytic system, mice were placed in a hypoxic environment with pO 2 Ͻ 40 Torr. Plasma levels of plasminogen activator inhibitor-1 (PAI-1) antigen, detected by ELISA, increased in a time-dependent fashion after hypoxic exposure (increased as early as 4 h, P Ͻ 0.05 vs. normoxic controls), and were accompanied by an increase in plasma PAI-1 activity by 4 h ( P Ͻ 0.05 vs. normoxic controls). Northern analysis of hypoxic murine lung demonstrated an increase in PAI-1 mRNA compared with normoxic controls; in contrast, transcripts for both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) decreased under hypoxic conditions. Immunocolocalization studies identified macrophages as the predominant source of increased PAI-1 within hypoxic lung. Using a transformed murine macrophage line, striking induction of PAI-1 transcripts occurred under hypoxic conditions, due to both increased de novo transcription as well as increased mRNA stability. Consistent with an important role of the fibrinolytic system in hypoxia-induced fibrin accumulation, PAI-1 ϩ / ϩ mice exposed to hypoxia exhibited increased pulmonary fibrin deposition based upon a fibrin immunoblot, intravascular fibrin identified by immunostaining, and increased accumulation of 125 I-fibrinogen/fibrin in hypoxic tissue. In contrast, mice deficient for the PAI-1 gene (PAI-1 Ϫ / Ϫ ) similarly exposed to hypoxic conditions did not display increased fibrin accumulation compared with normoxic PAI-1 ϩ / ϩ controls. Furthermore, homozygous null uPA (uPA Ϫ / Ϫ ) and tPA (tPA Ϫ / Ϫ ) mice subjected to oxygen deprivation showed increased fibrin deposition compared with wildtype controls. These studies identify enhanced expression of PAI-1 as an important mechanism suppressing fibrinolysis under conditions of low oxygen tension, a response which may be further amplified by decreased expression of plasminogen activators. Taken together, these data provide insight into an important potential role of macrophages and the fibrinolytic system in ischemia-induced thrombosis.

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Section: Resultsmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 62%

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Pinsky¹,

Liao²,

Lawson³

et al. 1998

J. Clin. Invest.

182

109

View full text Add to dashboard Cite

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“…24 -26 Ischemia in the form of reduced oxygen tension has been demonstrated to both induce synthesis of PAI-1 mRNA and antigen and reduce TPA antigen release from cultured endothelial cells. 27 It is possible that endothelial cells with the 2/2 PAI-1 genotype may be more susceptible to the effects of ischemia than other forms of the PAI-1 gene, resulting in a greater expression of PAI-1. This coupled with the reduction in TPA levels would significantly reduce fibrinolytic activity and possibly promote the early development of vasculopathy.…”

Section: Discussionmentioning

confidence: 99%

Gene Polymorphisms for Plasminogen Activator Inhibitor-1/Tissue Plasminogen Activator and Development of Allograft Coronary Artery Disease

et al. 1998

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Background-Impaired fibrinolytic activity has been linked to the presence and severity of allograft vasculopathy (Tx CAD). This impairment may be associated with the presence of certain fibrinolytic protein gene polymorphisms. Methods and Results-To investigate the relation between donor-specific fibrinolytic protein genotypes and Tx CAD, we identified donor plasminogen activator inhibitor-1 (PAI-1) HindIII and tissue plasminogen activator (TPA) EcoRI restriction fragment length polymorphisms-based genotypes by Southern blot analysis in 48 recipients of cardiac allografts and correlated these genotypes with the development of CAD. No association was found between donor TPA genotypes and the presence of Tx CAD. Among the 48 patients, 17% were homozygous for the 1/1 PAI-1 genotype, 51% for the 2/2 PAI-1 genotype, and 32% for the 1/2 PAI-1 genotype. The actuarial freedom from any CAD for the recipients with each respective donor PAI-1 genotype at 12 and 24 months was 100% and 100% for the 1/1 PAI-1 genotype, 92% and 92% for the 1/2 PAI-1 genotype, and 75% and 45% for the 2/2 PAI-1 genotype (Pϭ0.03). Recipients with a diseased 2/2 PAI-1 genotyped allograft had longer ischemic times (Pϭ0.02) than those recipients with a Tx CAD-free allograft. Conclusions-These data suggest that recipients with a 2/2 PAI-1 genotype are at a significant risk of developing Tx CAD.This genotype may serve as a useful screening tool for predicting the future development of Tx CAD. (Circulation. 1998;98:2248-2254.)

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“…[39][40][41] In accord with this concept are observations of intense PAI-1 expression in endothelial cells lining neovessels within chronically organizing pulmonary thromboemboli, which are also likely to be in a proliferative stage. 8 Furthermore, local hypoxia, which has been shown to be a trigger for PAI-1 upregulation, 42,43 could be another factor responsible for the elevation of PAI-1 in the remodeling/organization regions within the thrombi.…”

Section: Discussionmentioning

confidence: 99%

Elevated Expression of Urokinase-like Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 During the Vascular Remodeling Associated With Pulmonary Thromboembolism

Lang

Moser

Schleef

1998

ATVB

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Abstract-Information is lacking on the mechanisms involved in the organization, resolution, and repair of the vascular lumen after acute pulmonary thromboembolism. Because recent data suggest that the balance between plasminogen activators (PAs) and type 1 plasminogen activator inhibitor (PAI-1) plays a role in regulating cell migration within the extracellular matrix, we investigated the expression of these molecules by immunohistochemical and in situ hybridization analysis of pulmonary artery specimens from patients suffering fatal pulmonary embolism. The data were compared with the expression of these molecules in both patients' noninvolved pulmonary arteries and organ donor pulmonary arteries. Regions of initial organization and vascular remodeling were identified by a modified trichrome stain and by the presence of proliferating cell nuclear antigen (PCNA), a cell marker of proliferation. Staining for tissue-type PA antigen was low to undetectable in endothelial cells directly in contact with the fibrin-platelet thromboembolus and in areas in which the endothelial cell lining was replaced by cell growth into the thrombus. Urokinase-like PA (u-PA) expression was detected in mononuclear cells within the thrombus in the initial phase of thromboembolism and within cells migrating into the thrombus during the later stages of organization. PAI-1 expression was elevated in the monolayer of endothelial cells underlying the fresh platelet-fibrin thromboembolus and in a PCNA-positive cell population present between the pulmonary arterial intima and the thromboembolus that represents early organization. Increased expression of PAI-1 may play a role in inhibiting proteolysis and fostering the localization of the acute fibrin-platelet thrombus to the vascular wall, which is followed by the upregulation of u-PA in migrating cells during the reorganization process. (Arterioscler Thromb Vasc Biol. 1998;18:808-815.)Key Words: thrombus organization Ⅲ plasminogen activators Ⅲ plasminogen activator inhibitor type 1 Ⅲ pulmonary thromboembolism R ecognized venous thromboembolism, comprising both pulmonary embolism and deep venous thrombosis, leads to sudden death in about 10% of patients, accounting for about 300 000 clinical episodes and 50 000 deaths per year in the United States.1,2 The origin of thrombi embolizing to the lungs is in the great majority of cases the deep veins of the legs, particularly iliac, femoral, and popliteal veins.3 The morphological features of a fresh thromboembolus are similar to those of a nondetached thrombus, with alternating layers of platelets, fibrin, and erythrocytes.3 In addition to obstruction of the pulmonary trunk and/or both main pulmonary arteries, pulmonary embolism may progress slowly until the vascular bed has been reduced by multiple small pulmonary thromboemboli. In the latter situation, a single fresh thromboembolus suffices to cause acute right ventricular failure.Resolution of pulmonary thromboemboli is usually derived by mechanical fragmentation, endogenous thrombolysis, or repa...

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Ambient oxygen tension modulates endothelial fibrinolysis

Abstract: These data support the hypothesis of a fibrinolytic shift after altered ambient O2 tensions exposure in endothelium and demonstrate that HSVEC are more sensitive to altered O2 tension than HUVEC. Altered O2 tensions depress EC fibrinolysis in this model.

Cited by 68 publications

References 13 publications

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition.

Gene Polymorphisms for Plasminogen Activator Inhibitor-1/Tissue Plasminogen Activator and Development of Allograft Coronary Artery Disease

Elevated Expression of Urokinase-like Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 During the Vascular Remodeling Associated With Pulmonary Thromboembolism

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