Villefranc, J.A., Nicoli, S., Bentley, K., Jeltsch, M., Zarkada, G., Moore, J.C., Gerhardt, H., Alitalo, K., and Lawson, N.D. (2013) A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development. Development (Cambridge, England). 140(7):1497-1506.
Vascular endothelial growth factor C (Vegfc) is a secreted protein that guides lymphatic development in vertebrate embryos.
However, its role during developmental angiogenesis is not well characterized. Here, we identify a mutation in zebrafish vegfc that severely affects lymphatic development and leads to angiogenesis defects on sensitized genetic backgrounds. The um18 mutation prematurely truncated Vegfc, blocking its secretion and paracrine activity but not its ability to activate its receptor
Flt4. When expressed in endothelial cells, vegfcum18 could not rescue lymphatic defects in mutant embryos, but induced ectopic blood vessel branching. Furthermore, vegfc-deficient endothelial cells did not efficiently contribute to tip cell positions in developing sprouts. Computational modeling
together with assessment of endothelial cell dynamics by time-lapse analysis suggested that an autocrine Vegfc/Flt4 loop plays
an important role in migratory persistence and filopodia stability during sprouting. Our results suggest that Vegfc acts in
two distinct modes during development: as a paracrine factor secreted from arteries to guide closely associated lymphatic
vasculature and as an autocrine factor to drive migratory persistence during angiogenesis.