Remodeling of the vessel wall after copper-induced injury is highly attenuated in mice with a total deficiency of plasminogen activator inhibitor-1.

Abstract

Clinical studies have indicated that high plasma levels of fibrinogen, or decreased fibrinolytic potential, are conducive to an increased risk of cardiovascular disease. Other investigations have shown that insoluble fibrin promotes atherosclerotic lesion formation by affecting smooth muscle cell proliferation, collagen deposition, and cholesterol accumulation. To directly assess the physiological impact of an imbalanced fibrinolytic system on both early and late stages of this disease, mice deficient for plasminogen activator inhibitor-1 (PAI-1(-/-)) were used in a model of vascular injury/repair, and the resulting phenotype compared to that of wild-type (WT) mice. A copper-induced arterial injury was found to generate a lesion with characteristics similar to many of the clinical features of atherosclerosis. Fibrin deposition in the injured arterial wall at early (7 days) and late (21 days) times after copper cuff placement was prevalent in WT mice, but was greatly diminished in PAI-1(-/-) mice. A multilayered neointima with enhanced collagen deposition was evident at day 21 in WT mice. In contrast, only diffuse fibrin was identified in the adventitial compartments of arteries from PAI-1(-/-) mice, with no evidence of a neointima. Neovascularization was observed in the adventitia and was more extensive in WT arteries, relative to PAI-1(-/-) arteries. Additionally, enhanced PAI-1 expression and fat deposition were seen only in the arterial walls of WT mice. The results of this study emphasize the involvement of the fibrinolytic system in vascular repair processes after injury and indicate that alterations in the fibrinolytic balance in the vessel wall have a profound effect on the development and progression of vascular lesion formation.

• Authors: V A Ploplis, I Cornelissen, M J Sandoval-Cooper, L Weeks, F A Noria, F J Castellino
• Journal: The American journal of pathology (Am J Pathol) Vol. 158 Issue 1 Pg. 107-17 (Jan 2001) ISSN: 0002-9440 [Print] United States
• PMID: 11141484 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Lipoproteins, LDL
• Plasminogen Activator Inhibitor 1
• oxidized low density lipoprotein
• Copper

Topics

• Animals
• Blood Vessels (drug effects, pathology, physiopathology)
• Carotid Arteries (pathology, physiopathology, ultrastructure)
• Cell Division
• Copper (administration & dosage)
• Female
• Genotype
• Lipoproteins, LDL (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Electron
• Plasminogen Activator Inhibitor 1 (deficiency, genetics)
• Time Factors
• Tunica Intima (metabolism, pathology, physiopathology)
• Tunica Media (metabolism, pathology, physiopathology)