Inhibition of vascular smooth muscle cell proliferation by a novel fibroblast growth factor receptor antagonist.
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 IC(50) of approximately 1 microM 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.


CONCLUSIONS
We have identified an FGF antagonist, which may serve in clinical practice as a preventive measure of restenosis.
Segev
Amit
A
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Aviezer
David
D
Safran
Michal
M
Gross
Zeev
Z
Yayon
Avner
A
D000818:Animals; D001011:Aorta; D001667:Binding, Competitive; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D003864:Depression, Chemical; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D011166:Porphyrins / Q000494:pharmacology*; D011485:Protein Binding; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*
D011166:Porphyrins; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; C021096:tetra(4-N-methylpyridyl)porphine; D006493:Heparin; D004247:DNA