A mutant form of vascular endothelial growth factor (VEGF) that lacks VEGFreceptor-2 activation retains the ability to induce vascular permeability

Vascular endothelial growth factor (VEGF) is a major mediator of vasculogen esis and angiogenesis both during development and in pathological condition s. VEGF has a variety of effects on vascular endothelium, including the abi lity to stimulate endothelial cell mitogenesis, and the potent induction of vascular permeability. These activities are at least in part mediated by b inding to two high affinity receptors, VEGFR-1 and VEGFR-2, In this study w e have made mutations of mouse VEGF in order to define the regions that are required for VEGFR-2-mediated functions, Development of a bioassay, which responds only to signals generated by cross-linking of VEGFR-2, has allowed evaluation of these mutants for their ability to activate VEGFR-2, One mut ant (VEGF0), which had amino acids 83-89 of VEGF substituted with the analo gous region of the related placenta growth factor, demonstrated significant ly reduced VEGFR-2 binding compared with wild type VEGF, indicating that th is region was required for VEGF-VEGFR-2 interaction, Intriguingly, when thi s mutant was evaluated in a Miles assay for its ability to induce vascular permeability, no difference was found when compared with wild type VEGF, In addition we have shown that the VEGF homology domain of the structurally r elated growth factor VEGF-D is capable of binding to and activating VEGFR-2 but has no vascular permeability activity, indicating that VEGFR-2 binding does not correlate with permeability activity for all VEGF family members; These data suggest different mechanisms for VEGF-mediated mitogenesis and vascular permeability and raise the possibility of an alternative receptor mediating vascular permeability.