Structural features in heparin that interact with VEGF165 and modulate its biological activity

• Published in: Glycobiology (Oxford) Vol. 9; no. 7; pp. 705 - 711
• Main Authors: Ono, Katsuaki, Hattori, Hidemi, Takeshita, Sawako, Kurita, Akira, Ishihara, Masayuki
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.07.1999
• Subjects: Binding Sites; Carbohydrate Sequence; Cell Division - drug effects; Cells, Cultured; chemically modified heparin; Disaccharides - chemistry; Endothelial Growth Factors - metabolism; Endothelial Growth Factors - pharmacology; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Enzyme-Linked Immunosorbent Assay; Glycosaminoglycans - chemistry; Glycosaminoglycans - metabolism; heparan sulfate; heparin; Heparin - chemistry; Heparin - metabolism; Heparin - pharmacology; heparinoid; Humans; Lymphokines - metabolism; Lymphokines - pharmacology; Molecular Structure; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; VEGF165
• ISSN: 0959-6658; 1460-2423; 1460-2423
• DOI: 10.1093/glycob/9.7.705

The 165 amino acid form of vascular endothelial growth factor (VEGF165) is a heparin-binding growth factor with mitogenic activity for vascular endothelial cells. We examined activities of various heparin derivatives toward their interactions with VEGF165 using an enzyme-linked immunosorbent assay and elucidated the structural features in heparin for the interactions. Native heparin interacted with VEGF165, whereas N-desulfated, N-acetylated (N-DS, N-Ac-) heparin, and 6-O-desulfated (6-O-DS-) heparin did not. The 2-O-desulfated (2-O-DS-) heparin retained the ability for the interaction with VEGF165. In contrast, the 2-O-DS-heparin exhibited no ability for the interaction with FGF-2 and HGF. Thus, structural requirements in heparin for the specific interaction with VEGF165 are distinct from those with FGF-2 and HGF which require a high content of 2-O-sulfate groups. In a cell proliferation assay, native heparin and 2-O-DS-heparin exhibited inhibitory abilities for VEGF165-induced proliferation of human umbilical vein endothelial cells (HUVECs) with their high concentrations (more than 64 µg/ml), while only native heparin could enhance the proliferation of the chlorate-treated cells. These results suggested that a high content of 2-O-sulfate groups is not required for the specific interaction with VEGF165 alone, although it is essential for the mitogenic activity of the growth factor.