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YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation
Jongshin Kim, … , Dae-Sik Lim, Gou Young Koh
Jongshin Kim, … , Dae-Sik Lim, Gou Young Koh
Published August 14, 2017
Citation Information: J Clin Invest. 2017;127(9):3441-3461. https://doi.org/10.1172/JCI93825.
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Research Article Angiogenesis Development

YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation

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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.

Authors

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

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Figure 6

Endothelial YAP/TAZ is required for vascular network formation in brain.

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Endothelial YAP/TAZ is required for vascular network formation in brain....
(A) Diagram for EC-specific deletion of Yap/Taz in brain vessels from P2 and their analyses at P12 in Yap/TaziΔEC mice. (B and C) Images of CD31+ vessels of cerebral cortex and striatum, and comparisons of indicated parameters in WT and Yap/TaziΔEC mice (n = 5, each group). The yellow dashed line demarcates the border between cortex and striatum. Scale bars: 500 μm. (D and E) Magnified images of tip ECs and comparisons of indicated parameters in WT and Yap/TaziΔEC mice (n = 5, each group). Tip ECs of Yap/TaziΔEC mice exhibit an aneurysm-like structure with less and dysmorphic filopodia (white arrowheads). Scale bars: 25 μm. (F and G) Images and comparisons of levels of glucose transporter 1 (GLUT1), transferrin receptor (TfR), PLVAP, and PDGFRβ+ pericyte coverage onto CD31+ vessels in cerebral striatum of WT and Yap/TaziΔEC mice (n = 5, each group). Scale bars: 50 μm. (H) Diagram for EC-specific deletion of Yap/Taz from P2 and sampling of brain ECs and their analyses at P8 in Yap/TaziΔEC mice. (I) GSEA of isolated brain ECs showing downregulation of YAP signature genes in Yap/TaziΔEC compared with those in WT mice, and correspondent heatmaps of the top 15 enriched genes. ES, enrichment score; NES, normalized enrichment score. Error bars represent mean ± SD. *P < 0.05 vs. WT by Mann-Whitney U test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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