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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 8

VEGF upregulates YAP/TAZ transcriptional activity in ECs.

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VEGF upregulates YAP/TAZ transcriptional activity in ECs.
(A and B) Imag...
(A and B) Images and quantification of the nuclear enrichment of YAP in HUVECs stimulated with VEGF (50 ng/ml) for 30 minutes (n = 4, each group). Scale bars: 20 μm. (C and D) Immunoblot analyses and comparisons of indicated proteins in HUVECs stimulated with VEGF (50 ng/ml) for indicated times (n = 3, each group). Note that, upon VEGFR2 activation, the level of pLATS1 (Thr1079) is reduced after 5 minutes, and reduction in pYAP (Ser127) level follows after 30 minutes. (E) Quantitative PCR analysis of CTGF and CYR61 mRNA levels in HUVECs stimulated with VEGF for 1 hour (n = 4, each group). (F) GSEA of the microarray data (GSE18913) showing upregulation of YAP signature genes in HUVECs stimulated with VEGF for 1 hour compared with control. ES, enrichment score; NES, normalized enrichment score. Error bars and dots represent mean ± SD. *P < 0.05 vs. control or 0 minutes by Mann-Whitney U test.
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