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 for mation by human umbilical vein endothelial cells (HUVEC) on the basement me mbrane preparation, Matrigel. In this study, using more defined systems whe re basic fibroblast growth factor (bFGF) induces the tube formation by HUVE C on collagen gel, we investigated the mechanism responsible for the inhibi tion of angiogenesis by OSF in vitro. Unlike NF and desulfated fucoidan (de sF), OSF potently inhibited the bFGF-induced HUVEC migration and tube forma tion. ELISA for tissue-type plasminogen activator (t-PA) and plasminogen ac tivator inhibitor-1 (PAI-1) in the culture media indicated that OSF increas ed the bFGF-induced release of PAI-1 antigen, but not of t-PA antigen. Anal yses of the binding of bFGF to HUVEC surfaces and the following protein tyr osine phosphorylation revealed that OSF could promote the cell binding and autophosphorylation of 140 and 160 kDa receptors. In heparitinase-treated H UVEC, 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 requi red for binding to the high affinity receptors with tyrosine kinase activit y. The resultant increase in PAI-1 release may play a key role for the prev ention of cell migration accompanied by matrix proteolysis. (C) 2000 Elsevi er Science B.V. All rights reserved.