Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Huddinge, Sweden.
Stem Cells Dev. 2013 May 1;22(9):1360-9. doi: 10.1089/scd.2012.0259. Epub 2013 Feb 12.
Hypoxia (low oxygen) and Notch signaling are 2 important regulators of vascular development, but how they interact in controlling the choice between arterial and venous fates for endothelial cells during vasculogenesis is less well understood. In this report, we show that hypoxia and Notch signaling intersect in promotion of arterial differentiation. Hypoxia upregulated expression of the Notch ligand Dll4 and increased Notch signaling in a process requiring the vasoactive hormone adrenomedullin. Notch signaling also upregulated Dll4 expression, leading to a positive feedback loop sustaining Dll4 expression and Notch signaling. In addition, hypoxia-mediated upregulation of the arterial marker genes Depp, connexin40 (Gja5), Cxcr4, and Hey1 required Notch signaling. In conclusion, the data reveal an intricate interaction between hypoxia and Notch signaling in the control of endothelial cell differentiation, including a hypoxia/adrenomedullin/Dll4 axis that initiates Notch signaling and a requirement for Notch signaling to effectuate hypoxia-mediated induction of the arterial differentiation program.
缺氧（低氧）和 Notch 信号通路是血管发育的 2 个重要调节因子，但它们在血管发生过程中如何相互作用控制内皮细胞向动脉和静脉命运的选择还不太清楚。在本报告中，我们显示缺氧和 Notch 信号通路在促进动脉分化方面相互作用。缺氧上调了 Notch 配体 Dll4 的表达，并增加了血管活性激素肾上腺髓质素（adrenomedullin）所要求的 Notch 信号通路。Notch 信号通路也上调了 Dll4 的表达，形成一个正反馈回路，维持 Dll4 的表达和 Notch 信号通路。此外，缺氧介导的动脉标记基因 Depp、连接蛋白 40（Gja5）、Cxcr4 和 Hey1 的上调需要 Notch 信号通路。总之，这些数据揭示了缺氧和 Notch 信号通路在控制内皮细胞分化中的复杂相互作用，包括一个起始 Notch 信号通路的缺氧/肾上腺髓质素/Dll4 轴，以及 Notch 信号通路对缺氧介导的动脉分化程序的诱导的要求。
