YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation

Jongshin Kim; Yoo Hyung Kim; Jaeryung Kim; Do Young Park; Hosung Bae; Da-Hye Lee; Kyun Hoo Kim; Seon Pyo Hong; Seung Pil Jang; Yoshiaki Kubota; Young-Guen Kwon; Dae-Sik Lim; Gou Young Koh

doi:10.1172/JCI93825

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YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation

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YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation

Jongshin Kim, Yoo Hyung Kim, Jaeryung Kim, Do Young Park, Hosung Bae, Da-Hye Lee, Kyun Hoo Kim, Seon Pyo Hong, Seung Pil Jang, Yoshiaki Kubota, …

The Journal of clinical investigation, Vol.127(9), pp.3441-3461

09/01/2017

DOI: 10.1172/JCI93825

PMID: 28805663

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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.

Details

Title: Subtitle: YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation
Creators: Jongshin Kim - Korea Advanced Institute of Science and Technology
Yoo Hyung Kim - Korea Advanced Institute of Science and Technology
Jaeryung Kim - Korea Advanced Institute of Science and Technology
Do Young Park - Korea Advanced Institute of Science and Technology
Hosung Bae - Korea Advanced Institute of Science and Technology
Da-Hye Lee - Creative Research
Kyun Hoo Kim - Korea Advanced Institute of Science and Technology
Seon Pyo Hong - Institute for Basic Science
Seung Pil Jang - Korea Advanced Institute of Science and Technology
Yoshiaki Kubota - Keio University
Young-Guen Kwon
Dae-Sik Lim
Gou Young Koh - Korea Advanced Institute of Science and Technology
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.127(9), pp.3441-3461
DOI: 10.1172/JCI93825
PMID: 28805663
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Number of pages: 21
Grant note: IBS-R025-D1-2015 / the Institute for Basic Science funded by the Ministry of Science, ICT and Future Planning, Korea
Language: English
Date published: 09/01/2017
Academic Unit: Internal Medicine
Record Identifier: 9985217131602771

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