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Multiple mechanisms for exogenous heparin modulation of vascular endothelial growth factor activity
Author(s) -
Wijelath Errol,
Namekata Mayumi,
Murray Jacqueline,
Furuyashiki Mai,
Zhang Siyuan,
Coan Daniel,
Wakao Masahiro,
Harris Robert B.,
Suda Yasuo,
Wang Lianchun,
Sobel Michael
Publication year - 2010
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22727
Subject(s) - heparin , modulation (music) , microbiology and biotechnology , growth factor , chemistry , biology , biochemistry , receptor , physics , acoustics
Heparin and heparin‐like molecules are known to modulate the cellular responses to vascular endothelial growth factor‐A (VEGF‐A). In this study, we investigated the likely mechanisms for heparin's influence on the biological activity of VEGF‐A. Previous studies have shown that exogenous heparin's effects on the biological activity of VEGF‐A are many and varied, in part due to the endogenous cell‐surface heparan sulfates. To circumvent this problem, we used mutant endothelial cells lacking cell‐surface heparan sulfates. We showed that VEGF‐induced cellular responses are dependent in part on the presence of the heparan sulfates, and that exogenous heparin significantly augments VEGF's cellular effects especially when endogenous heparan sulfates are absent. Exogenous heparin was also found to play a cross‐bridging role between VEGF‐A 165 and putative heparin‐binding sites within its cognate receptor, VEGFR2 when they were examined in isolation. The cross‐bridging appears to be more dependent on molecular weight than on a specific heparin structure. This was confirmed by surface plasmon resonance binding studies using sugar chips immobilized with defined oligosaccharide structures, which showed that VEGF‐A 165 binds to a relatively broad range of sulfated glycosaminoglycan structures. Finally, studies of the far‐UV circular dichroism spectra of VEGF‐A 165 showed that heparin can also modulate the conformation and secondary structure of the protein. J. Cell. Biochem. 111: 461–468, 2010. © 2010 Wiley‐Liss, Inc.