Intermittent hypoxia is an angiogenic inducer for endothelial cells: role of HIF-1.

The presence of hypoxia in tumor and its role in promoting angiogenesis are well-established. Recently, in addition to chronic hypoxia, cycling or intermittent hypoxia has also been demonstrated. However, its role in inducing new blood vessel formation is less clear. This work is aimed to investigate whether intermittent hypoxia can induce a pro-angiogenic phenotype in endothelial cells, in vitro. We studied changes in the expression of genes involved in inflammation and angiogenesis under intermittent and chronic hypoxia. We evidenced genes specifically expressed under intermittent hypoxia, suggesting different cell responses induced by intermittent versus chronic hypoxia. An increase in the expression of pro-angiogenic and pro-inflammatory genes under intermittent hypoxia, translating a pro-angiogenic effect of intermittent hypoxia was detected. In parallel, we investigated the activity of three transcription factors known to be activated either under hypoxia or by reoxygenation: HIF-1, Nrf2, and NF-kappaB. HIF-1alpha stabilization and an increase in HIF-1 transcriptional activity were evidenced under intermittent hypoxia. On the other hand, NRF2 and NF-kappaB transcription factors were not activated. Finally, an increase in endothelial cell migration and in tubulogenesis in the course of hypoxia-reoxygenation cycles was evidenced, which was inhibited by HIF-1alpha siRNA. All together, these results demonstrate a clear pro-angiogenic effect of intermittent hypoxia.