AVIAN VEGF-C - CLONING, EMBRYONIC EXPRESSION PATTERN AND STIMULATION OF THE DIFFERENTIATION OF VEGFR2-EXPRESSING ENDOTHELIAL-CELL PRECURSORS

VEGF-C is a recently discovered secreted polypeptide related to the an giogenic mitogen VEGF, We have isolated the quail VEGF-C cDNA and show n that its protein product is secreted from transfected cells and inte racts with the avian VEGFR3 and VEGFR2, In situ hybridization shows th at quail VEGF-C mRNA is strongly expressed in regions destined to be r ich in lymphatic vessels, particularly the mesenteries, mesocardium an d myotome, in the region surrounding the jugular veins, and in the kid ney, These expression sites are similar to those observed in the mouse embryo (E, Kukk, A, Lymboussaki, S, Taira, A, Kaipainen, M, Jeltsch, V. Joukov and K. Alitalo, 1996, Development 122, 3829-3837), We have o bserved VEGFR3-positive endothelial cells in proximity to most of the VEGF-C-expressing sites, suggesting functional relationships between t his receptor-ligand couple, The comparison of the VEGF and VEGFR2 knoc kout phenotypes had suggested the existence of another ligand for VEGF R2, We therefore investigated the effect of VEGF-C on VEGFR2-positive cells isolated from the posterior mesoderm of gastrulating embryos, We have recently shown that VEGF binding triggers endothelial differenti ation of these cells, whereas hemopoietic differentiation appears to b e mediated by binding of a so far unidentified VEGFR2 ligand, We show here that VEGF-C also triggers endothelial differentiation of these ce lls, presumably via VEGFR2, These results indicate that VEGF and VEGF- C can act in a redundant manner via VEGFR2, In conclusion, VEGF-C appe ars to act during two different developmental phases, one early in pos terior mesodermal VEGFR2-positive endothelial cell precursors which ar e negative for VEGFR3 and one later in regions rich in lymphatic vesse ls at a time when endothelial cells express both VEGFR2 and VEGFR3.