TY - JOUR AU - Yasuda, Daisuke AU - Kobayashi, Daiki AU - Akahoshi, Noriyuki AU - Ohto-Nakanishi, Takayo AU - Yoshioka, Kazuaki AU - Takuwa, Yoh AU - Mizuno, Seiya AU - Takahashi, Satoru AU - Ishii, Satoshi T1 - Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4 PY - 2019/10/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI121955 VL - 129 IS - 10 UR - https://doi.org/10.1172/JCI121955 SP - 4332 EP - 4349 PB - The American Society for Clinical Investigation ER -