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

Yoo Hyung Kim, Jeongwoon Choi, Myung Jin Yang, Seon Pyo Hong, Choong kun Lee, Yoshiaki Kubota, Dae Sik Lim, Gou Young Koh

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Article number838
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

Fingerprint

angiogenesis
Cell Polarity
Mitochondria
Endothelial cells
Reactive Oxygen Species
hypoxia
polarity
cascades
Endothelial Cells
Genes
Oxygen
cells
Cell Nucleus Active Transport
deletion
Cell Movement
mitochondria
impairment
oxygen
genes
mice

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

A MST1–FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis. / Kim, Yoo Hyung; Choi, Jeongwoon; Yang, Myung Jin; Hong, Seon Pyo; Lee, Choong kun; Kubota, Yoshiaki; Lim, Dae Sik; Koh, Gou Young.

In: Nature communications, Vol. 10, No. 1, 838, 01.12.2019.

Research output: Contribution to journalArticle

Kim, Yoo Hyung ; Choi, Jeongwoon ; Yang, Myung Jin ; Hong, Seon Pyo ; Lee, Choong kun ; Kubota, Yoshiaki ; Lim, Dae Sik ; Koh, Gou Young. / A MST1–FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis. In: Nature communications. 2019 ; Vol. 10, No. 1.
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