한빛사 논문
Yoo Hyung Kim1, Jeongwoon Choi2,3, Myung Jin Yang2,3, Seon Pyo Hong3, Choong-kun Lee1,3, Yoshiaki Kubota4, Dae-Sik Lim5 & Gou Young Koh1,3,*
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.
*Correspondence and requests for materials should be addressed to G.Y.K.
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.
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