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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 4

DLL4 expression is negatively regulated by LPA through LPA4/LPA6–Gα12/Gα13–Rho–ROCK signaling in ECs.

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DLL4 expression is negatively regulated by LPA through LPA4/LPA6–Gα12/Gα...
(A) LPA (10 μM, 3 hours) affected mRNA expression of various angiogenesis-related genes in serum-starved HUVECs. (B and C) LPA (10 μM) reduced mRNA (B) and protein (C) expression of DLL4 in a time-dependent manner in serum-starved HUVECs. (D) LPA4 and/or LPA6 siRNAs increased mRNA expression of DLL4. (E) LPA4/LPA6 and Gα12/Gα13 siRNAs increased protein expression of DLL4. (F) LPA4/LPA6 siRNAs increased protein expression of DLL4 and abolished the suppressive effect of LPA (10 μM, 3 hours) in serum-starved HUVECs. (G) Y27632 (10 μM, 10 minutes pretreatment) but not Ki16425 (10 μM, 10 minutes pretreatment) increased mRNA expression of DLL4 and abolished the suppressive effect of LPA (10 μM, 3 hours) in serum-starved HUVECs. (H) Rho inhibitor I (0.5 μg/mL, 6 hours pretreatment) and Y27632 (10 μM, 10 minutes pretreatment) increased protein expression of DLL4 and abolished the suppressive effect of LPA (10 μM, 3 hours) in serum-starved HUVECs. (I and J) Mouse lung ECs from Lpa4fl/Y;Lpa6fl/fl;Tie2-Cre (Lpa4;Lpa6ΔEC) mice displayed increased Dll4 (I) and Hey1 (J) mRNA expression. (K) Scheme for how LPA–LPA4/LPA6–Gα12/Gα13–Rho–ROCK signaling suppresses DLL4 expression. Data are mean ± SEM of triplicates. *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA followed by Dunnett’s (B and D) or Tukey’s multiple-comparisons test (G) or 2-tailed unpaired Student’s t test (I and J). HUVECs were serum-starved for 8 hours or transfected with siRNAs for 96 hours. Unprocessed original scans of Western blots are shown in Supplemental Figure 12.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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