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- Title
Lysophosphatidic acid-induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4.
- Authors
Daisuke Yasuda; Daiki Kobayashi; Noriyuki Akahoshi; Takayo Ohto-Nakanishi; Kazuaki Yoshioka; Yoh Takuwa; Seiya Mizuno; Satoru Takahashi; Satoshi Ishii; Yasuda, Daisuke; Kobayashi, Daiki; Akahoshi, Noriyuki; Ohto-Nakanishi, Takayo; Yoshioka, Kazuaki; Takuwa, Yoh; Mizuno, Seiya; Takahashi, Satoru; Ishii, Satoshi
- Abstract
Lysophosphatidic acid (LPA) is a potent lipid mediator with various biological functions mediated through six G protein-coupled receptors (GPCRs), LPA1-6. 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 (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 β-catenin- and Notch intracellular domain (NICD)-mediated endothelial expression of the Notch ligand delta-like 4 (DLL4). 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. Of note, 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 a novel insight into the biology of GPCR-activated YAP/TAZ.
- Subjects
G protein coupled receptors; NEOVASCULARIZATION; FIBRIN; EMBRYOLOGY; LYSOPHOSPHOLIPIDS; ENDOTHELIAL cells
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 10, p4332
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI121955