Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1

Orf virus, a member of the poxvirus family, produces a pustular dermatitis in sheep, goats, and humans. The lesions induced after infection with orf v irus show extensive proliferation of vascular endothelial cells, dilation o f blood vessels and dermal swelling. An explanation for the nature of these lesions may lie in the discovery that orf virus encodes an apparent homolo g of the mammalian vascular endothelial growth factor (VEGF) family of mole cules, These molecules mediate endothelial cell proliferation, vascular per meability, angiogenesis, and lymphangiogenesis via the endothelial cell rec eptors VEGFR-1 (Flt1), VEGFR-2 (KDR/Flk1), and VEGFR-3 (PIM). The VEGF-like protein of orf virus strain NZ2 (ORFV2-VEGF) is most closely related in pr imary structure to VEGF, In this study we examined the biological activitie s and receptor specificity of the ORFV2-VEGF protein. ORFV2-VEGF was found to be a disulfide-linked homodimer with a subunit of approximate to 25 kDa, ORFV2-VEGF showed mitogenic activity on bovine aortic and human microvascu lar endothelial cells and induced vascular permeability. ORFV2-VEGF was fou nd to bind and induce autophosphorylation of VEGFR-2 and was unable to bind or activate VEGFR-1 and VEGFR-3, but bound the newly identified VEGF(165) receptor neuropilin-1, These results indicate that, from a functional viewp oint, ORFV2-VEGF is indeed a member of the VEGF family of molecules, but is unique, however, in that it utilizes only VEGFR-2 and neuropilin-1.