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

Research output: Contribution to journalArticle

93 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3441-3461
Number of pages21
JournalJournal of Clinical Investigation
Volume127
Issue number9
DOIs
Publication statusPublished - 2017 Sep 1

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Kim, J., Kim, Y. H., Kim, J., Park, D. Y., Bae, H., Lee, D. H., Kim, K. H., Hong, S. P., Jang, S. P., Kubota, Y., Kwon, Y. G., Lim, D. S., & Koh, G. Y. (2017). YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. Journal of Clinical Investigation, 127(9), 3441-3461. https://doi.org/10.1172/JCI93825