Zeng Gefei, Taylor Sarah M, McColm Janet R, Kappas Nicholas C, Kearney Joseph B, Williams Lucy H, Hartnett Mary E, Bautch Victoria L
Department of Biology, University of North Carolina at Chapel Hill 27599, USA.
Blood. 2007 Feb 15;109(4):1345-52. doi: 10.1182/blood-2006-07-037952. Epub 2006 Oct 26.
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.
新血管形成需要内皮细胞分裂与血管扩张的形态发生运动相协调，但目前尚不清楚这种整合是如何发生的。在这里，我们表明，内皮细胞在血管形成的最早阶段，响应形态发生线索来调节分裂方向。在没有血流的胚胎干细胞（ES）来源的血管中，内皮细胞胞质分裂平面垂直于血管长轴。我们还在体内有血流的正在形成的视网膜血管中证明了有调控的分裂方向。子核在分裂后从分裂平面移开，这表明内皮分裂方向的调控有效地延长了这些发育中的血管床的长度。VEGF信号通路的功能获得性突变增加了内皮分裂方向的随机性，而这种效应可通过转基因得到挽救，这表明分裂方向的调控是VEGF信号通路影响血管形态发生的一种新机制。因此，我们的研究结果表明，内皮细胞分裂和形态发生在发育中的血管中通过涉及VEGF信号通路的非血流依赖机制整合在一起，这种相互作用可能对血管的正常形态发生至关重要。
