Format

Send to

Choose Destination
Nat Commun. 2019 Feb 19;10(1):838. doi: 10.1038/s41467-019-08773-2.

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

Author information

1
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea.
2
Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon, 34141, Korea.
3
Center for Vascular Research, Institute for Basic Science (IBS), Daejeon, 34141, Korea.
4
Department of Vascular Biology, The Sakaguchi Laboratory, Keio University School of Medicine, Tokyo, 160-8582, Japan.
5
National Creative Research Initiatives Center for Cell Division and Differentiation, Department of Biological Science, KAIST, Daejeon, 34141, Korea.
6
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea. gykoh@kaist.ac.kr.
7
Center for Vascular Research, Institute for Basic Science (IBS), Daejeon, 34141, Korea. gykoh@kaist.ac.kr.

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.

PMID:
30783090
PMCID:
PMC6381131
DOI:
10.1038/s41467-019-08773-2
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center