TY - JOUR
T1 - A MST1–FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis
AU - Kim, Yoo Hyung
AU - Choi, Jeongwoon
AU - Yang, Myung Jin
AU - Hong, Seon Pyo
AU - Lee, Choong kun
AU - Kubota, Yoshiaki
AU - Lim, Dae Sik
AU - Koh, Gou Young
N1 - Funding Information:
We thank Intae Park (KAIST) for proofreading of the manuscript; Hosung Bae, Sun-Hye Jeong, and Daehee Hwang (KAIST) for providing experiment protocols and critical comments; Yu Sam Mi, Sujin Seo, and Hye jin Choi for their technical assistance. This study was supported by the Institute for Basic Science funded by the Ministry of Science, ICT and Future Planning, Korea (IBS-R025-D1-2015 to G.Y.K.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-08773-2
DO - 10.1038/s41467-019-08773-2
M3 - Article
C2 - 30783090
AN - SCOPUS:85061826557
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 838
ER -