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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 1

Endothelial YAP/TAZ is a crucial regulator of vascular sprouting and growth.

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Endothelial YAP/TAZ is a crucial regulator of vascular sprouting and gro...
(A) Diagram for EC-specific depletion of YAP/TAZ in retinal vessels from P2 and their analyses at P5 using Yap/TaziΔEC mice. (B and C) Images of CD31+ retinal vessels and comparisons of indicated parameters in WT and Yap/TaziΔEC mice (n = 5, each group). Scale bars: 500 μm. (D and E) Magnified images and comparisons of retinal vessels in the vascular front region of WT and Yap/TaziΔEC mice at P5 (n = 5, each group). Tip ECs in Yap/TaziΔEC mice exhibit an aneurysm-like structure with less and dysmorphic filopodia (yellow arrowheads). Scale bars: 100 μm, top panels; 50 μm, bottom panels. (F) Images showing phalloidin+ actin filament (F-actin) bundle and ICAM2+/collagen IV+ (COL4+) lumen formation in tip ECs of WT and Yap/TaziΔEC mice. No organized F-actin bundle–containing protrusions and defective lumen formation (white arrowhead) are detected in tip ECs of Yap/TaziΔEC mice. Scale bars: 50 μm. (G and H) Images and comparisons of ERG+ ECs, pHH3+ proliferating ECs (white arrowheads), and cl-CASP3+ apoptotic ECs in WT and Yap/TaziΔEC mice (n = 5, each group). Scale bars: 100 μm. Error bars represent mean ± SD. *P < 0.05 vs. WT by Mann-Whitney U test.
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ISSN: 0021-9738 (print), 1558-8238 (online)

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