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J Clin Invest. 2017 Sep 1;127(9):3441-3461. doi: 10.1172/JCI93825. Epub 2017 Aug 14.

YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation.

Kim J1, Kim YH1,2, Kim J1,2, Park DY1,2, Bae H1,2, Lee DH3, Kim KH1,2, Hong SP1,2, Jang SP1,2, Kubota Y4, Kwon YG5, Lim DS3, Koh GY1,2.

Author information

1
Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.
2
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
3
National Creative Research Initiatives Center for Cell Division and Differentiation, Department of Biological Science, KAIST, Daejeon, South Korea.
4
Department of Vascular Biology, The Sakaguchi Laboratory, Keio University School of Medicine, Tokyo, Japan.
5
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.

Abstract

Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases.

PMID:
28805663
PMCID:
PMC5669570
DOI:
10.1172/JCI93825
[Indexed for MEDLINE]
Free PMC Article

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