Oversulfated fucoidan inhibits the basic fibroblast growth factor-induced tube formation by human umbilical vein endothelial cells: its possible mechanism of action.
We have previously demonstrated that chemically oversulfated fucoidan (OSF) but not native fucoidan (NF) effectively suppresses the tube structure formation by human umbilical vein endothelial cells (HUVEC) on the basement membrane preparation, Matrigel. In this study, using more defined systems where basic fibroblast growth factor (bFGF) induces the tube formation by HUVEC on collagen gel, we investigated the mechanism responsible for the inhibition of angiogenesis by OSF in vitro. Unlike NF and desulfated fucoidan (desF), OSF potently inhibited the bFGF-induced HUVEC migration and tube formation. ELISA for tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in the culture media indicated that OSF increased the bFGF-induced release of PAI-1 antigen, but not of t-PA antigen. Analyses of the binding of bFGF to HUVEC surfaces and the following protein tyrosine phosphorylation revealed that OSF could promote the cell binding and autophosphorylation of 140 and 160 kDa receptors. In heparitinase-treated HUVEC, contrarily, the bFGF binding and PAI-1 release were decreased by OSF. These results suggest that OSF is a highly sulfated unique polysaccharide that can promote the binding of bFGF to the heparan sulfate molecules required for binding to the high affinity receptors with tyrosine kinase activity. The resultant increase in PAI-1 release may play a key role for the prevention of cell migration accompanied by matrix proteolysis.
Soeda
S
S
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, 814-0180, Fukuoka, Japan.
Kozako
T
T
Iwata
K
K
Shimeno
H
H
D001667:Binding, Competitive; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism / Q000494:pharmacology*; D013431:Sulfates / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000187:drug effects / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
D019812:Heparan Sulfate Proteoglycans; D017395:Plasminogen Activator Inhibitor 1; D011134:Polysaccharides; D013431:Sulfates; D016222:Fibroblast Growth Factor 2; C007789:fucoidan; D010959:Tissue Plasminogen Activator