TY - JOUR T1 - A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development. JF - Development Y1 - 2013 AB -

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, vegfc(um18) 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.

VL - 140 IS - 7 ER - TY - JOUR T1 - VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia JF - J Cell Biol Y1 - 2003 A1 - Gerhardt, Holger A1 - Golding, Matthew A1 - Fruttiger, Marcus A1 - Ruhrberg, Christiana A1 - Lundkvist, Andrea A1 - Abramsson, Alexandra A1 - Jeltsch, Michael A1 - Mitchell, Christopher A1 - Alitalo, Kari A1 - Shima, David A1 - Betsholtz, Christer AB - Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells. VL - 161 UR - http://view.ncbi.nlm.nih.gov/pubmed/12810700 IS - 6 JO - The Journal of Cell Biology ER -