Hypoxia-Induced Arterial Differentiation Requires Adrenomedullin and Notch Signaling

被引:23
|
作者
Lanner, Fredrik [1 ]
Lee, Kian Leong [2 ]
Ortega, German C. [3 ]
Sohl, Marcus [3 ]
Li, Xiujuan [4 ]
Jin, Shaobo [3 ]
Hansson, Emil M. [3 ]
Claesson-Welsh, Lena [4 ]
Poellinger, Lorenz [2 ,3 ]
Lendahl, Urban [3 ]
Farnebo, Filip [3 ]
机构
[1] Karolinska Inst, Dept Clin Sci Intervent & Technol, SE-14152 Huddinge, Sweden
[2] Natl Univ Singapore, Canc Sci Inst Singapore, Ctr Translat Med, Canc Biol Program, Singapore 117548, Singapore
[3] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden
[4] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden
基金
英国医学研究理事会;
关键词
EMBRYONIC STEM-CELLS; ENDOTHELIAL-CELLS; VASCULAR DEVELOPMENT; MICE LACKING; INDUCIBLE FACTOR; HYDROPS-FETALIS; RBP-J; VEGF; GENE; EXPRESSION;
D O I
10.1089/scd.2012.0259
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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.
引用
收藏
页码:1360 / 1369
页数:10
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