A NOVEL VASCULAR ENDOTHELIAL GROWTH-FACTOR, VEGF-C, IS A LIGAND FOR THE FLT4 (VEGFR-3) AND KDR (VEGFR-2) RECEPTOR TYROSINE KINASES

Angiogenesis, the sprouting of new blood vessels from pre-existing one s, and the permeability of blood vessels are regulated by vascular end othelial growth factor (VEGF) via its two known receptors Flt1 (VEGFR- 1) and KDR/Flk-1 (VEGFR-2). The Flt4 receptor tyrosine kinase is relat ed to the VEGF receptors, but does not bind VEGF and its expression be comes restricted mainly to lymphatic endothelia during development. In this study, we have purified the Flt4 ligand, VEGF-C, and cloned its cDNA from human prostatic carcinoma cells, While VEGF-C is homologous to other members of the VEGF/platelet derived growth factor (PDGF) fam ily, its C-terminal half contains extra cysteine-rich motifs character istic of a protein component of silk produced by the larval salivary g lands of the midge, Chironomas tentans, VEGF-C is proteolytically proc essed, binds Flt4, which we rename as VEGFR-3 and induces tyrosine aut ophosphorylation of VEGFR-3 and VEGFR-2. In addition, VEGF-C stimulate d the migration of bovine capillary endothelial cells in collagen gel, VEGF-C is thus a novel regulator of endothelia, and its effects may e xtend beyond the lymphatic system, where FIM is expressed.