title: Viral vascular endothelial growth factors vary extensively in amino acid sequence, receptor-binding specificities, and the ability to induce vascular permeability yet are uniformly active mitogens.
abstract: Infections of humans and ungulates by parapoxviruses result in skin lesions characterized by extensive vascular changes that have been linked to viral-encoded homologues of vascular endothelial growth factor (VEGF). VEGF acts via a family of receptors (VEGFRs) to mediate endothelial cell proliferation, vascular permeability, and angiogenesis. The VEGF genes from independent parapoxvirus isolates show an extraordinary degree of inter-strain sequence variation. We conducted functional comparisons of five representatives of the divergent viral VEGFs. These revealed that despite the sequence divergence, all were equally active mitogens, stimulating proliferation of human endothelial cells in vitro and vascularization of sheep skin in vivo with potencies equivalent to VEGF. This was achieved even though the viral VEGFs bound VEGFR-2 less avidly than did VEGF. Surprisingly the viral VEGFs varied in their ability to cross-link VEGFR-2, induce vascular permeability and bind neuropilin-1. Correlations between these three activities were detected. In addition it was possible to correlate these functional variations with certain sequence and structural motifs specific to the viral VEGFs. In contrast to the conserved ability to bind human VEGFR-2, the viral growth factors did not bind either VEGFR-1 or VEGFR-3. We propose that the extensive sequence divergence seen in the viral VEGFs was generated primarily by selection against VEGFR-1 binding.
authors.affiliation: Virus Research Unit, Department of Microbiology, University of Otago, P.O. Box 56, Dunedin, New Zealand.
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Wise
authors.forename: Norihito
authors.initials: N
authors.lastname: Ueda
authors.forename: Nicola H
authors.initials: NH
authors.lastname: Dryden
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fleming
authors.forename: Carol
authors.initials: C
authors.lastname: Caesar
authors.forename: Sally
authors.initials: S
authors.lastname: Roufail
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Mercer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002199:Capillary Permeability; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D039942:Neuropilin-1 / Q000378:metabolism; D011212:Poxviridae / Q000737:chemistry* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry* / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2