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 experience flow, the plane of endothelial cytokinesis 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 orientation 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 affects vessel morphogenesis. Thus, our findings show that endothelial cell division and morphogenesis are integrated in developing vessels by flow-independent mechanisms that involve VEGF signaling, and this cross talk is likely to be critical to proper vessel morphogenesis.
Zeng
Gefei
G
Department of Biology, University of North Carolina at Chapel Hill 27599, USA.
Taylor
Sarah M
SM
McColm
Janet R
JR
Kappas
Nicholas C
NC
Kearney
Joseph B
JB
Williams
Lucy H
LH
Hartnett
Mary E
ME
Bautch
Victoria L
VL
D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000254:growth & development; D002455:Cell Division; D053595:Embryonic Stem Cells; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D018919:Neovascularization, Physiologic; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000172:deficiency / Q000502:physiology*
C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1