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Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas

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Abstract

Forkhead box protein O1 (FoxO1) is a transcription factor and a critical regulator of angiogenesis. Various environmental stimuli, including growth factors, nutrients, shear stress, oxidative stress and hypoxia, affect FoxO1 subcellular localization and strongly influence its transcriptional activity; however, FoxO1-localization patterns in endothelial cells (ECs) during development have not been clarified in vivo. Here, we reported that FoxO1 expression was observed in three layers of angiogenic vessels in developing mouse retinas and that among these layers, the front layer showed high levels of FoxO1 expression in the nuclei of most tip ECs. Because tip ECs migrate toward the avascular hypoxic area, we focused on hypoxia as a major stimulus regulating FoxO1 subcellular localization in tip cells. In cultured ECs, FoxO1 accumulated into the nucleus under hypoxic conditions, with hypoxia also inducing expression of tip-cell-specific genes, including endothelial-specific molecule 1 (ESM1), which was suppressed by FoxO1 knockdown. Additionally, in murine models, EC-specific FoxO1 deletion resulted in reduced ESM1 expression and suppressed tip-cell migration during angiogenesis. These findings indicated roles for FoxO1 in tip-cell migration and that its transcriptional activity is regulated by hypoxia.

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Acknowledgements

We thank Dr. Bernd Arnold for Tie2CreER T 2mice and Manabu Sakai for helpful discussion.

Funding

This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (24590258 and 15K08142 to TF; 16K08442 to SI).

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Authors and Affiliations

  1. Group of Neurobiology, Division of Health Science, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka, 565-0871, Japan

    Moe Fukumoto, Kanako Kondo, Kazumasa Uni, Tomoko Ishiguro, Mikiko Hayashi, Shinnosuke Ueda, Itsuki Mori, Kenta Niimi & Shinobu Inagaki

  2. Department of Stem Cell Regulation Research, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan

    Fumi Tashiro, Satsuki Miyazaki & Jun-Ichi Miyazaki

  3. Kagawa Prefectural University of Health Sciences, Hara 281-1, Mure, Takamatsu, Kagawa, 761-0123, Japan

    Tatsuo Furuyama

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  1. Moe Fukumoto
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  3. Kazumasa Uni
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Correspondence to Shinobu Inagaki or Tatsuo Furuyama.

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Fukumoto, M., Kondo, K., Uni, K. et al. Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas. Angiogenesis 21, 203–214 (2018). https://doi.org/10.1007/s10456-017-9588-z

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  • DOI: https://doi.org/10.1007/s10456-017-9588-z

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