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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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PLENARY PAPER

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

Gefei Zeng1, Sarah M. Taylor1, Janet R. McColm2, Nicholas C. Kappas1, Joseph B. Kearney3, Lucy H. Williams3, Mary E. Hartnett2,4, and Victoria L. Bautch1,3,4

1 Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC; 2 Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, NC; 3 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC; 4 Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, NC

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.


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