A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases

The different members of the vascular endothelial growth factor (VEGF) fami ly act as key regulators of endothelial cell function controlling vasculoge nesis, angiogenesis, vascular permeability and endothelial cell survival. I n this study, we have functionally characterized a novel member of the VEGF family, designated VEGF-E. VEGF-E sequences are encoded by the para-poxvir us Orf virus (OV). They carry the characteristic cysteine knot motif presen t in all mammalian VEGFs, while forming a microheterogenic group distinct f rom previously described members of this family. VEGF-E was expressed as th e native protein in mammalian cells or as a recombinant protein in Escheric hia coil and was shown to act as a heat-stable, secreted dimer, VEGF-E and VEGF-A were found to possess similar bioactivities, i.e. both factors stimu late the release of tissue factor (TF), the proliferation, chemotaxis and s prouting of cultured vascular endothelial cells in vitro and angiogenesis i n vivo. Like VEGF-A, VEGF-E was found to bind with high affinity to VEGF re ceptor-2 (KDR) resulting in receptor autophosphorylation and a biphasic ris e in free intracellular Ca2+ concentration, whilst in contrast to VEGF-A, V EGF-E did not bind to VEGF receptor-1 (Flt-1), VEGF-E is thus a potent angi ogenic factor selectively binding to VEGF receptor-2, These data strongly i ndicate that activation of VEGF receptor-2 alone can efficiently stimulate angiogenesis.