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A MST1–FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis

Author

Listed:
  • Yoo Hyung Kim

    (Korea Advanced Institute of Science and Technology (KAIST))

  • Jeongwoon Choi

    (KAIST
    Institute for Basic Science (IBS))

  • Myung Jin Yang

    (KAIST
    Institute for Basic Science (IBS))

  • Seon Pyo Hong

    (Institute for Basic Science (IBS))

  • Choong-kun Lee

    (Korea Advanced Institute of Science and Technology (KAIST)
    Institute for Basic Science (IBS))

  • Yoshiaki Kubota

    (Keio University School of Medicine)

  • Dae-Sik Lim

    (KAIST)

  • Gou Young Koh

    (Korea Advanced Institute of Science and Technology (KAIST)
    Institute for Basic Science (IBS))

Abstract

Hypoxia is a main driver of sprouting angiogenesis, but how tip endothelial cells are directed to hypoxic regions remains poorly understood. Here, we show that an endothelial MST1–FOXO1 cascade is essential for directional migration of tip cells towards hypoxic regions. In mice, endothelial‐specific deletion of either MST1 or FOXO1 leads to the loss of tip cell polarity and subsequent impairment of sprouting angiogenesis. Mechanistically, MST1 is activated by reactive oxygen species (ROS) produced in mitochondria in response to hypoxia, and activated MST1 promotes the nuclear import of FOXO1, thus augmenting its transcriptional regulation of polarity and migration‐associated genes. Furthermore, endothelial MST1‐FOXO1 cascade is required for revascularization and neovascularization in the oxygen-induced retinopathy model. Together, the results of our study delineate a crucial coupling between extracellular hypoxia and an intracellular ROS‐MST1‐FOXO1 cascade in establishing endothelial tip cell polarity during sprouting angiogenesis.

Suggested Citation

  • Yoo Hyung Kim & Jeongwoon Choi & Myung Jin Yang & Seon Pyo Hong & Choong-kun Lee & Yoshiaki Kubota & Dae-Sik Lim & Gou Young Koh, 2019. "A MST1–FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08773-2
    DOI: 10.1038/s41467-019-08773-2
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    Cited by:

    1. Haifeng Zhang & Busu Li & Qunhua Huang & Francesc López-Giráldez & Yoshiaki Tanaka & Qun Lin & Sameet Mehta & Guilin Wang & Morven Graham & Xinran Liu & In-Hyun Park & Anne Eichmann & Wang Min & Jenny, 2022. "Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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