Vascular Biology Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK.
Nat Cell Biol. 2010 Oct;12(10):943-53. doi: 10.1038/ncb2103. Epub 2010 Sep 26.
Sprouting angiogenesis requires the coordinated behaviour of endothelial cells, regulated by Notch and vascular endothelial growth factor receptor (VEGFR) signalling. Here, we use computational modelling and genetic mosaic sprouting assays in vitro and in vivo to investigate the regulation and dynamics of endothelial cells during tip cell selection. We find that endothelial cells compete for the tip cell position through relative levels of Vegfr1 and Vegfr2, demonstrating a biological role for differential Vegfr regulation in individual endothelial cells. Differential Vegfr levels affect tip selection only in the presence of a functional Notch system by modulating the expression of the ligand Dll4. Time-lapse microscopy imaging of mosaic sprouts identifies dynamic position shuffling of tip and stalk cells in vitro and in vivo, indicating that the VEGFR-Dll4-Notch signalling circuit is constantly re-evaluated as cells meet new neighbours. The regular exchange of the leading tip cell raises novel implications for the concept of guided angiogenic sprouting.
发芽血管生成需要内皮细胞的协调行为，由 Notch 和血管内皮生长因子受体 (VEGFR) 信号调节。在这里，我们使用计算建模和遗传镶嵌发芽实验在体外和体内研究内皮细胞在尖端细胞选择过程中的调节和动力学。我们发现，内皮细胞通过相对水平的 Vegfr1 和 Vegfr2 竞争尖端细胞位置，证明了个体内皮细胞中 VEGFR 调节的生物学作用。只有在 Notch 系统功能正常的情况下，通过调节配体 Dll4 的表达，差异 VEGFR 水平才会影响尖端选择。镶嵌芽的延时显微镜成像在体外和体内识别出尖端和茎细胞的动态位置交换，表明 VEGFR-Dll4 Notch 信号通路随着细胞遇到新的邻居而不断重新评估。领先的尖端细胞的定期交换为有引导的血管生成发芽的概念提出了新的含义。
