Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis
Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis
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DOI：
10.1096/fj.04-3172fje
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发表时间：
2005-03-01
期刊：
影响因子：
4.8
通讯作者：
Hughes, CCW
中科院分区：
文献类型：
--
作者：
Sainson, RCA;Aoto, J;Hughes, CCW
在血管发育过程中对notch信号传导的需求是有据可查的，但了解甚少。胚胎和成人内皮细胞（EC）表达notch和notch配体，然而，血管生成过程中细胞自主notch信号的必要性尚未确定。在血管生成过程中，EC显示可塑性，从而使先前静止的细胞的子集失去极性并变得迁移。为了研究notch在EC中的作用，我们使用了一个三维体外系统，该系统模拟了血管生成的所有早期步骤。我们发现，新形成的芽是由专门的尖端细胞，引导芽和干细胞增殖和重新排列，形成细胞间腔。此外，我们发现，缺口行为细胞自主抑制EC增殖，从而调节管径。此外，当notch信号传导被阻断时，尖端细胞分裂，并且两个子细胞都呈现尖端细胞表型，导致通过血管分叉的分支增加。相反，notch信号传导对于EC极性的重建或管腔形成是不需要的。因此，notch被EC粘附性地和细胞自主地用于调节血管直径，限制芽尖处的分支，并建立成熟的静止表型。
The requirement for notch signaling during vascular development is well-documented but poorly understood. Embryonic and adult endothelial cells (EC) express notch and notch ligands; however, the necessity for cell-autonomous notch signaling during angiogenesis has not been determined. During angiogenesis, EC display plasticity, whereby a subset of previously quiescent cells loses polarity and becomes migratory. To investigate the role of notch in EC, we have used a three-dimensional in vitro system that models all of the early steps of angiogenesis. We find that newly forming sprouts are composed of specialized tip cells that guide the sprout and trunk cells that proliferate and rearrange to form intercellular lumens. Furthermore, we find that notch acts cell-autonomously to suppress EC proliferation, thereby regulating tube diameter. In addition, when notch signaling is blocked, tip cells divide, and both daughter cells take on a tip cell phenotype, resulting in increased branching through vessel bifurcation. In contrast, notch signaling is not required for re-establishment of EC polarity or for lumen formation. Thus, notch is used reiteratively and cell-autonomously by EC to regulate vessel diameter, to limit branching at the tip of sprouts, and to establish a mature, quiescent phenotype.