P330	Role of the factor VII activating protease (FSAP) in vascular smooth muscle cell proliferation and neointima formation.
1D.Sedding, 1J-M.Daniel, 1L.Muhl, 2H.Brunsch, 1K.Hersemeyer, 3R.Braun-Dullaeus, 2H.Tillmanns, 4B.Kemkes-Matthes, 1K.Preissner, 1S.Kanse
1Biochemistry - Giessen University, Gießen, DE; 2Cardiology - Giessen University, Gießen, DE; 3Cardiology - Dresden University of Technology, Dresden, DE; 4Hematology - Giessen University, Gießen, DE.

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: FSAP was strongly expressed in VSMC of uninjured vessels. In contrast, there was only week immunoreactivity in VSMC of the developing neointima. To reconstitute the FSAP content in neointimal VSMC, WT- or MI-FSAP (1 mg/mouse) was applied topically in pluronic F-127 gel around the denuded artery. Application of WT-FSAP 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 was necessary for the inhibition of neointimal thickening, since co-application of aprotinin or the specific inhibitor PPAC reversed this inhibition. Furthermore, a complete absence of fibrin(ogen) deposition and a significantly reduced accumulation of monocytes / macrophages was observed in WT-FSAP-treated vessels. 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 was 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.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.