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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1345-1352.
Prepublished online as a Blood First Edition Paper on October 26, 2006; DOI 10.1182/blood-2006-07-037952.
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Submitted July 27, 2006
Accepted October 3, 2006
The orientation of endothelial cell division is
regulated by VEGF signaling during blood vessel formation
Gefei Zeng, Sarah M Taylor, Janet R McColm, Nicholas C Kappas, Joseph B Kearney, Lucy H Williams, M E Hartnett, and Victoria L Bautch*
Dept of Biology, The University of North Carolina at Chapel Hill, NC
Dept of Ophthalmology, The University of North Carolina at Chapel Hill, NC
Curriculum in Genetics & Molecular Biology, The University of North Carolina at Chapel Hill, NC
Carolina Cardiovascular Biology Center, The University of North Carolina at Chapel Hill, NC
* Corresponding author; email: bautch{at}med.unc.edu.
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 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 impacts 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.
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