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

Clinical studies have indicated that high plasma levels of fibrinogen, or d ecreased fibrinolytic potential, are conducive to an increased risk of card iovascular disease. Other investigations have shown that insoluble fibrin p romotes atherosclerotic lesion formation by affecting smooth muscle cell pr oliferation, collagen deposition, and cholesterol accumulation. To directly assess the physiological impact of an imbalanced frbrinolytic system on bo th early and late stages of this disease, mite deficient for plasminogen ac tivator inhibitor-1 (PAI-1(-/-)) were used in a model of vascular injury/re pair, and the resulting phenotype compared to that of wild-type (WT) mice. A. copper-induced arterial injury was found to generate a lesion with chara cteristics similar to many of the clinical features of atherosclerosis, Fib rin 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 g reatly diminished in PAI-1(-/-) mice. A multilayered neointima with enhance d collagen deposition was evident at day 21 in WT mice. In contrast, only d iffuse fibrin was identified in the adventitial compartments of arteries fr om 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 de position were seen only in the arterial walls of WT mice. The results of th is study emphasize the involvement of the fibrinolytic system in vascular r epair processes after injury and indicate that alterations in the fibrinoly tic balance in the vessel wall have a profound effect on the development an d progression of vascular lesion formation.