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.
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.
Ogawa
S
S
Department of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639 Japan.
Oku
A
A
Sawano
A
A
Yamaguchi
S
S
Yazaki
Y
Y
Shibuya
M
M
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002199:Capillary Permeability / Q000187:drug effects; D019281:Dimerization; D004730:Endothelium, Vascular / Q000187:drug effects; D004789:Enzyme Activation; D019143:Evolution, Molecular; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000098:blood supply; D051379:Mice; D008934:Mitogens / Q000235:genetics / Q000494:pharmacology*; D018919:Neovascularization, Physiologic; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1; D014764:Viral Proteins / Q000235:genetics / Q000494:pharmacology*
D008934:Mitogens; D011518:Proto-Oncogene Proteins; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; C084758:VEGF-like protein, Orf virus; D014764:Viral Proteins; D006493:Heparin; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1