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

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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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2019-02
Language
English
Article Type
Article
Citation

NATURE COMMUNICATIONS, v.10

ISSN
2041-1723
DOI
10.1038/s41467-019-08773-2
URI
http://hdl.handle.net/10203/251638
Appears in Collection
BS-Journal Papers(저널논문)MSE-Journal Papers(저널논문)
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