Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate.

Authors:
Holger Diez
Holger Diez
Theodor-Boveri-Institute
Germany
Andreas Fischer
Andreas Fischer
School of Chemical Science and Engineering
Sweden
Anja Winkler
Anja Winkler
Theodor-Boveri-Institute
Germany
Dr. Cheng-Jun Hu, PhD
Dr. Cheng-Jun Hu, PhD
University of Colorado
Associate Professor
Pulmonary hypertension
Aurora, CO | United States
Antonis K Hatzopoulos
Antonis K Hatzopoulos
Vanderbilt University
United States
Georg Breier
Georg Breier
Dresden University of Technology
Germany
Manfred Gessler
Manfred Gessler
Theodor-Boveri-Institute/Biocenter
Germany

Exp Cell Res 2007 Jan 19;313(1):1-9. Epub 2006 Sep 19.

Theodor-Boveri-Institute, Physiological Chemistry I, Biocenter of the University of Wurzburg, Am Hubland, 97074 Wuerzburg, Germany.

Adequate response to low oxygen levels (hypoxia) by hypoxia inducible factor (HIF) is essential for normal development and physiology, but this pathway may also contribute to pathological processes like tumor angiogenesis. Here we show that hypoxia is an inducer of Notch signaling. Hypoxic conditions lead to induction of the Notch ligand Dll4 and the Notch target genes Hey1 and Hey2 in various cell lines. Promoter analysis revealed that Hey1, Hey2 and Dll4 are induced by HIF-1alpha and Notch activation. Hypoxia-induced Notch signaling may also determine endothelial identity. Endothelial progenitor cells (EPCs) contain high amounts of COUP-TFII, a regulator of vein identity, while levels of the arterial regulators Dll4 and Hey2 are low. Hypoxia-mediated upregulation of Dll4 and Hey2 leads to repression of COUP-TFII in eEPCs. Finally, we show that Hey factors are capable of repressing HIF-1alpha-induced gene expression, suggesting a negative feedback loop to prevent excessive hypoxic gene induction. Thus, reduced oxygen levels lead to activation of the Dll4-Notch-Hey2 signaling cascade and subsequent repression of COUP-TFII in endothelial progenitor cells. We propose that this is an important step in the developmental regulation of arterial cell fate decision.

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Source
http://dx.doi.org/10.1016/j.yexcr.2006.09.009DOI Listing
January 2007
18 Reads
65 Citations
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