YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation

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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.
Publisher
AMER SOC CLINICAL INVESTIGATION INC
Issue Date
2017-09
Language
English
Article Type
Article
Keywords

BLOOD-BRAIN-BARRIER; ENDOTHELIAL TIP CELLS; HIPPO PATHWAY; CHOROIDAL NEOVASCULARIZATION; VESSEL FORMATION; ACTIN-BINDING; RHO GTPASES; YAP; ANGIOPOIETIN-2; METABOLISM

Citation

JOURNAL OF CLINICAL INVESTIGATION, v.127, no.9, pp.3447 - 3467

ISSN
0021-9738
DOI
10.1172/JCI93825
URI
http://hdl.handle.net/10203/226128
Appears in Collection
BS-Journal Papers(저널논문)MSE-Journal Papers(저널논문)
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