Zebrafish G protein {gamma}2 is required for VEGF signaling during angiogenesis

Vascular endothelial growth factor (VEGF) is a major mediator of pathological angiogenesis, a process necessary for the formation of new blood vessels to support tumor growth. Historically, VEGF is thought to signal via receptor tyrosine kinases, which are not typically considered to be G protein dependent. Here, we show that targeted knockdown of the G protein gng2 gene (Ggamma2) blocks the normal angiogenic process in developing zebrafish embryos. Moreover, loss of gng2 function inhibits the ability of VEGF to promote the angiogenic sprouting of blood vessels by attenuating VEGF induced phosphorylation of phospholipase C-gamma1 (PLCgamma1) and serine/threonine kinase (AKT). Collectively, these results demonstrate a novel interaction between Ggamma2- and VEGF-dependent pathways to regulate the angiogenic process in a whole animal model. Blocking VEGF function using a humanized anti-VEGF antibody has emerged as a promising treatment for colorectal, non-small lung cell, and breast cancers. However, this treatment may cause considerable side effects. Our findings provide a new opportunity for co-targeting G protein- and VEGF-dependent pathways to synergistically block pathological angiogenesis, which may lead to a safer and more efficacious therapeutic regimen to fight cancer.