1: FEBS J. 2009 Jan;276(2):509-18. Epub 2008 Dec 10.

Impact of cyclic hypoxia on HIF-1alpha regulation in endothelial cells--new
insights for anti-tumor treatments.

Martinive P, Defresne F, Quaghebeur E, Daneau G, Crokart N, Grégoire V, Gallez B,
Dessy C, Feron O.

Unit of Pharmacology and Therapeutics, Université catholique de Louvain,
Brussels, Belgium.

Heterogeneities in tumor blood flow are associated with cyclic changes in pO2 or 
cyclic hypoxia. A major difference from O2 diffusion-limited or chronic hypoxia
is that the tumor vasculature itself may be directly influenced by the
fluctuating hypoxic environment, and the reoxygenation phases complicate the
usual hypoxia-induced phenotypic pattern. Here, we determined the cyclic
hypoxia-driven pathways that modulate hypoxia inducible factor (HIF)-1alpha
abundance in endothelial cells to identify possible therapeutic targets. We found
that exposure of endothelial cells to cycles of hypoxia/reoxygenation led to
accumulation of HIF-1alpha during the hypoxic periods and the phosphorylation of 
protein kinase B (Akt), extracellular regulated kinase (ERK) and endothelial
nitric oxide synthase (eNOS) during the reoxygenation phases. We identified
stimulation of mitochondrial respiration and activation of the phosphoinositide-3
kinase (PI3K)/Akt pathway during intervening reoxygenation periods as major
triggers of the stabilization of HIF-1alpha. We also found that the NOS inhibitor
nitro-l-arginine methyl ester further stimulated the cyclic hypoxia-driven
HIF-1alpha accumulation and the associated gain in endothelial cell survival,
thereby mirroring the effects of a PI3K/Akt inhibitor. However, combination of
both drugs resulted in a net reduction in HIF-1alpha and a dramatic in decrease
in endothelial cell survival. In conclusion, this study identified cyclic
hypoxia, as reported in many tumor types, as a unique biological challenge for
endothelial cells that promotes their survival in a HIF-1alpha-dependent manner
through phenotypic alterations occurring during the reoxygenation periods. These 
observations also indicate the potential of combining Akt-targeting drugs with
anti-angiogenic drugs, in particular those interfering with the NO pathway.


PMID: 19077164 [PubMed - indexed for MEDLINE]

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