A Novel Type of Vascular Endothelial Growth Factor, VEGF-E (NZ-7 VEGF), Preferentially Utilizes KDR/Flk-1 Receptor and Carries a Potent Mitotic Activity without Heparin-binding Domain

• Published in: The Journal of biological chemistry 1998-11, Vol.273 (47), p.31273-31282
• Main Authors: Ogawa, Sachiyo, Oku, Asuka, Sawano, Asako, Yamaguchi, Sachiko, Yazaki, Yoshio, Shibuya, Masabumi
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Binding, Competitive; Capillary Permeability - drug effects; Dimerization; Endothelium, Vascular - drug effects; Enzyme Activation; Evolution, Molecular; Heparin - metabolism; Humans; Liver - blood supply; Mice; Mitogens - genetics; Mitogens - pharmacology; Neovascularization, Physiologic; Protein Conformation; Proto-Oncogene Proteins - metabolism; Rats; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Fibroblast Growth Factor - metabolism; Receptors, Growth Factor - metabolism; Receptors, Platelet-Derived Growth Factor - metabolism; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Vascular Endothelial Growth Factor Receptor-1; Viral Proteins - genetics; Viral Proteins - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.47.31273

Vascular endothelial growth factor (VEGF) mediates endothelial cell proliferation, angiogenesis, and vascular permeability via the endothelial cell receptors, KDR/Flk-1 and Flt-1. Recently, a gene encoding a polypeptide with about 25% amino acid identity to mammalian VEGF was identified in the genome of Orf virus (OV), a parapoxvirus that affects sheep and goats and occasionally, humans, to generate lesions with angiogenesis. In this study, we examined the biological activities and receptor of OV-derived NZ-7 VEGF (VEGF-E). VEGF-E was found to be a dimer of about 20 kDa with no basic domain nor affinity for heparin column, similar to VEGF121 subtype. VEGF121 has 10–100-fold less endothelial cell mitotic activity than VEGF165 due to lack of a heparin-binding basic region. Interestingly, however, VEGF-E showed almost equal levels of mitotic activity on primary endothelial cells and vascular permeability activity as VEGF165. Furthermore, VEGF-E bound KDR/Flk-1 (VEGFR-2) and induced its autophosphorylation to almost the same extent as VEGF165, but did not bind Flt-1 (VEGFR-1) nor induce autophosphorylation of Flt-1. These results indicate that VEGF-E is a novel type of endothelial growth factor, utilizing only one of the VEGF receptors, and carrying a potent mitogenic activity without affinity to heparin.