Hypoxia-induced arterial differentiation requires adrenomedullin and notch signaling

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adrenomedullin / genetics
  • Adrenomedullin / metabolism*
  • Animals
  • Arteries / cytology*
  • Arteries / physiology
  • Calcium-Binding Proteins
  • Cell Differentiation
  • Cell Hypoxia
  • Cells, Cultured
  • Embryoid Bodies / metabolism
  • Endothelial Cells / physiology
  • Gene Expression Regulation
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Neovascularization, Physiologic
  • Receptors, Notch / metabolism
  • Signal Transduction*
  • Transcriptome
  • Vascular Endothelial Growth Factor A / metabolism


  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • DLL4 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Notch
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Adrenomedullin