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Angiogenesis

, Volume 21, Issue 2, pp 203–214 | Cite as

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

  • Moe Fukumoto
  • Kanako Kondo
  • Kazumasa Uni
  • Tomoko Ishiguro
  • Mikiko Hayashi
  • Shinnosuke Ueda
  • Itsuki Mori
  • Kenta Niimi
  • Fumi Tashiro
  • Satsuki Miyazaki
  • Jun-Ichi Miyazaki
  • Shinobu Inagaki
  • Tatsuo Furuyama
Original Paper

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.

Keywords

Tip-cell Migration Hypoxia Forkhead transcription factor ESM1 Mouse retina 

Notes

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).

Supplementary material

10456_2017_9588_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 15 kb)
10456_2017_9588_MOESM2_ESM.jpg (160 kb)
Supplementary material 2 (JPEG 159 kb)

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Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2017

Authors and Affiliations

  1. 1.Group of Neurobiology, Division of Health Science, Graduate School of MedicineOsaka UniversitySuitaJapan
  2. 2.Department of Stem Cell Regulation Research, Graduate School of MedicineOsaka UniversitySuitaJapan
  3. 3.Kagawa Prefectural University of Health SciencesTakamatsuJapan

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