Plenary paper Orientation of endothelial cell division is regulated by VEGF signaling during blood vessel formation

New blood vessel formation requires the coordination of endothelial cell division and the morphogenetic movements of vessel expansion, but it is not known how this integration occurs. Here, we show that endothelial cells regulate division orientation during the earliest stages of blood vessel formation, in response to morphogenetic cues. In embryonic stem (ES) cell–derived vessels that do not expe-rience flow, the plane of endothelial cyto-kinesis was oriented perpendicular to the vessel long axis. We also demonstrated regulated cleavage orientation in vivo, in flow-exposed forming retinal vessels. Daughter nuclei moved away from the cleavage plane after division, suggesting that regulation of endothelial division ori-entation effectively extends vessel length in these developing vascular beds. A gain-of-function mutation in VEGF signaling increased randomization of endothelial division orientation, and this effect was rescued by a transgene, indicating that regulation of division orientation is a novel mechanism whereby VEGF signaling af-fects vessel morphogenesis. Thus, our findings show that endothelial cell divi-sion and morphogenesis are integrated in developing vessels by flow-independent mechanisms that involve VEGF signal-ing, and this cross talk is likely to be critical to proper vessel morphogenesis