Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Röntgenstrasse 20, D-48149 Münster, Germany.
Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, D-35392 Giessen, Germany.
Nat Cell Biol. 2017 Aug;19(8):915-927. doi: 10.1038/ncb3555. Epub 2017 Jul 17.
Endothelial sprouting and proliferation are tightly coordinated processes mediating the formation of new blood vessels during physiological and pathological angiogenesis. Endothelial tip cells lead sprouts and are thought to suppress tip-like behaviour in adjacent stalk endothelial cells by activating Notch. Here, we show with genetic experiments in postnatal mice that the level of active Notch signalling is more important than the direct Dll4-mediated cell-cell communication between endothelial cells. We identify endothelial expression of VEGF-A and of the chemokine receptor CXCR4 as key processes controlling Notch-dependent vessel growth. Surprisingly, genetic experiments targeting endothelial tip cells in vivo reveal that they retain their function without Dll4 and are also not replaced by adjacent, Dll4-positive cells. Instead, activation of Notch directs tip-derived endothelial cells into developing arteries and thereby establishes that Dll4-Notch signalling couples sprouting angiogenesis and artery formation.
内皮细胞的出芽和增殖是紧密协调的过程，介导了生理和病理血管生成过程中新生血管的形成。内皮细胞的尖端细胞引导出芽，并通过激活 Notch 来抑制相邻的茎状内皮细胞的尖端样行为。在这里，我们通过对出生后小鼠的遗传实验表明，活性 Notch 信号的水平比内皮细胞之间直接的 Dll4 介导的细胞间通讯更为重要。我们发现，内皮细胞表达 VEGF-A 和趋化因子受体 CXCR4 是控制 Notch 依赖性血管生长的关键过程。令人惊讶的是，针对体内内皮细胞尖端细胞的遗传实验表明，它们在没有 Dll4 的情况下保留其功能，也不会被相邻的 Dll4 阳性细胞所取代。相反，Notch 的激活将尖端衍生的内皮细胞定向到正在发育的动脉中，从而建立了 Dll4-Notch 信号传导将出芽血管生成和动脉形成联系起来。
