Sa. Stacker et al., A mutant form of vascular endothelial growth factor (VEGF) that lacks VEGFreceptor-2 activation retains the ability to induce vascular permeability, J BIOL CHEM, 274(49), 1999, pp. 34884-34892
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.