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Impact of cyclic hypoxia on HIF‐1α regulation in endothelial cells – new insights for anti‐tumor treatments

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)‐1α 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‐1α 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‐1α. We also found that the NOS inhibitor nitro‐l‐arginine methyl ester further stimulated the cyclic hypoxia‐driven HIF‐1α 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‐1α 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‐1α‐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.