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Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4
Daisuke Yasuda, … , Satoru Takahashi, Satoshi Ishii
Daisuke Yasuda, … , Satoru Takahashi, Satoshi Ishii
Published July 23, 2019
Citation Information: J Clin Invest. 2019;129(10):4332-4349. https://doi.org/10.1172/JCI121955.
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Research Article Angiogenesis

Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4

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Abstract

Lysophosphatidic acid (LPA) is a potent lipid mediator with various biological functions mediated through six G protein–coupled receptors (GPCRs), LPA1–LPA6. Previous studies have demonstrated that LPA–Gα12/Gα13 signaling plays an important role in embryonic vascular development. However, the responsible LPA receptors and underlying mechanisms are poorly understood. Here, we show a critical role of LPA4 and LPA6 in developmental angiogenesis. In mice, Lpa4;Lpa6 double-knockout (DKO) embryos were lethal due to global vascular deficiencies, and endothelial cell–specific (EC-specific) Lpa4;Lpa6-DKO retinas had impaired sprouting angiogenesis. Mechanistically, LPA activated the transcriptional regulators YAP and TAZ through LPA4/LPA6–mediated Gα12/Gα13–Rho–ROCK signaling in ECs. YAP/TAZ knockdown increased endothelial expression of the Notch ligand delta-like ligand 4 (DLL4) that was mediated by β-catenin and Notch intracellular domain (NICD). Fibrin gel sprouting assay revealed that LPA4/LPA6, Gα12/Gα13, or YAP/TAZ knockdown consistently blocked EC sprouting, which was rescued by a Notch inhibitor. Notably, the inhibition of Notch signaling also ameliorated impaired retinal angiogenesis in EC-specific Lpa4;Lpa6-DKO mice. Overall, these results suggest that the Gα12/Gα13–coupled receptors LPA4 and LPA6 synergistically regulate endothelial Dll4 expression through YAP/TAZ activation. This could in part account for the mechanism of YAP/TAZ–mediated developmental angiogenesis. Our findings provide insight into the biology of GPCR-activated YAP/TAZ.

Authors

Daisuke Yasuda, Daiki Kobayashi, Noriyuki Akahoshi, Takayo Ohto-Nakanishi, Kazuaki Yoshioka, Yoh Takuwa, Seiya Mizuno, Satoru Takahashi, Satoshi Ishii

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Figure 10

Nuclear YAP suppresses DLL4 expression in a TEAD-independent manner.

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Nuclear YAP suppresses DLL4 expression in a TEAD-independent manner.
(A ...
(A and B) TEAD1–4 siRNAs had no significant effect on mRNA (A) or protein (B) expression of DLL4. (C and D) Overexpression of YAP WT and 5SA and S94A mutants reduced mRNA (C) and protein (D) expression of DLL4 in sparse HUVECs. (E and F) Overexpression of the YAP 5SA mutant reduced mRNA (E) and protein (F) expression of DLL4 in overconfluent HUVECs. Data are mean ± SEM of triplicates. ***P < 0.001, 1-way ANOVA followed by Dunnett’s multiple-comparisons test. Unprocessed original scans of Western blots are shown in Supplemental Figure 14.
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