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 and Gou Young Koh ()
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Yoo Hyung Kim: Korea Advanced Institute of Science and Technology (KAIST)
Jeongwoon Choi: KAIST
Myung Jin Yang: KAIST
Seon Pyo Hong: Institute for Basic Science (IBS)
Choong-kun Lee: Korea Advanced Institute of Science and Technology (KAIST)
Yoshiaki Kubota: Keio University School of Medicine
Dae-Sik Lim: KAIST
Gou Young Koh: Korea Advanced Institute of Science and Technology (KAIST)

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08773-2

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