Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1)and KDR (VEGFR-2) - A reassessment using novel receptor-specific vascular endothelial growth factor mutants

Endothelial cells express two related vascular endothelial growth factor (V EGF) receptor tyrosine kinases, KDR (kinase-insert domain containing recept or, or VEGFR-2) and Flt-1 (fms-like tyrosine kinase, or VEGFR-1). Although considerable experimental evidence links KDR activation to endothelial cell mitogenesis, there is still significant uncertainty concerning the role of individual VEGF receptors for other biological effects such as vascular pe rmeability, VEGF mutants that bind to either KDR or Fit-1 with high selecti vity were used to determine which of the two receptors serves to mediate di fferent VEGF functions. In addition to mediating mitogenic signaling, selec tive KDR activation was sufficient for the activation of intracellular sign aling pathways implicated in cell migration. KDR stimulation caused tyrosin e phosphorylation of both phosphatidylinositol 3-kinase and phospholipase C gamma in primary endothelial cells and stimulated cell migration. KDR-sele ctive VEGF was also able to induce angiogenesis in the rat cornea to an ext ent indistinguishable from wild type VEGF, We also demonstrate that KDR, bu t not Flt-1, stimulation is responsible for the induction of vascular perme ability by VEGF.