Abstract 1541: The Factor VII Activating Protease Inhibits Neointima Formation and the G534E Polymorphism is Associated with Cardiovascular Risk Due to a Loss of this Activity
Background: We previously described that FSAP, a plasma serine-protease that is localized within atherosclerotic lesions, can bind to growth factors and inhibit vascular smooth muscle (VSMC) proliferation and migration. The FSAP-Marburg I (MI) polymorphism (G511E) is associated with late complications of carotid stenosis and thromboembolism. In this study we investigated the effect of wild type (WT) and MI-FSAP, isolated from patients homozygous for the MI genotype, on neointima formation in the mouse femoral artery after wire-induced injury.
Methods and Results: There was a strong FSAP expression in VSMC of uninjured vessels but hardly any FSAP immunoreactivity in VSMC of the developing neointima. Immediately after injury, WT- or MI-FSAP (1 μg/mouse) was applied topically in pluronic F-127 gel around the denuded artery. Reduced fibrin(ogen) deposition and a significantly reduced accumulation of monocytes / macrophages was observed in WT-FSAP-treated vessels. Application of WT-FSAP also significantly reduced the number of proliferating (PCNA positive) cells and resulted in a 75% reduction in neointima/media ratio compared to placebo 21 days after injury. The enzymatic activity of WT-FSAP is relevant for the inhibition of neointimal thickening, since protease inhibition using the specific inhibitor PPAC reversed this inhibition. In contrast, MI-FSAP had no influence on fibrin(ogen) accumulation, VSMC proliferation in vitro and in vivo or neointima formation. MI-FSAP exhibited much lower proteolytic activity towards pro-urokinase as compared to WT-FSAP. Furthermore, the reduction in neointima/media ratio with WT-FSAP was significantly less in urokinase −/ − mice compared to WT-mice, indicating that enzymatic pro-urokinase activation is a likely mechanism for the observed effects of FSAP.
Conclusion: These observations could explain the linkage between the MI polymorphism, with loss of ability to activate pro-urokinase, and the increased disposition to the development of vascular lesions / -complications. Hence, FSAP has an antiproliferative / protective function in the vasculature and may be useful for preventing vascular proliferative diseases.