© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Inhibition of vascular smooth muscle cell proliferation by a novel fibroblast growth factor receptor antagonist
aDepartment of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
bDepartment of Cardiology, Meir General Hospital, Kfar-Saba and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
cProChon Biotech Ltd, Weizmann Science Park, Rehovot, Israel
dDepartment of Chemistry, Technion – Israel Institute of Technology, Haifa, Israel
* Corresponding author. Tel.: +972-8-940-1570; fax: +972-8-930-1208 avner.yayon{at}weizmann.ac.il
Objective: One of the key events in post-angioplasty restenosis is the migration and proliferation of medial smooth muscle cells leading to neo-intima formation. This phase is mediated by several growth factors, mainly platelet-derived growth factor (PDGF), basic fibroblast growth factor (FGF2/bFGF) and heparin-binding epidermal growth factor (HB-EGF). In this study, we have focused on the role of FGF2, which requires heparan sulfate proteoglycans (HSPG) as cofactors for binding and activation of its cell surface tyrosine kinase receptor. The aim of this study was to identify and explore the effect of novel FGF antagonists on vascular smooth muscle cell (VSMC) proliferation. Methods: We have recently identified a novel class of small, positively charged molecules sharing a porphyrin core as inhibitors of FGF2 and vascular endothelial growth factor (VEGF) activity. Here we investigated the inhibitory effect of these compounds on VSMC proliferation and their effect on heparin-induced FGF receptor activity. Results: We found that these molecules exert a marked inhibitory effect on FGF2-mediated smooth muscle cell (SMC) proliferation, manifested by reduced cell growth and DNA synthesis, which occurred in a dose-dependent manner with an IC50 of 
1 µM of inhibitor. We demonstrate that the molecule, 5, 10, 15, 20-tetrakis (methyl-4-pyridyl)-21H, 23H-porphine tetra-p-tosylate salt (TMPP), inhibits binding of radiolabeled FGF2 to SMCs and to soluble FGF receptor 1 (FGFR1) in a manner that interferes with both ligand and receptor interactions with heparin, thereby blocking growth factor mediated SMC proliferation. Conclusion: We have identified an FGF antagonist, which may serve in clinical practice as a preventive measure of restenosis.
KEYWORDS Growth factors; Smooth muscle; Restenosis
This work was presented in part at the American Heart Association 71st Scientific Sessions.
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