Format

Send to

Choose Destination
J Clin Invest. 2019 Jul 23;130:4332-4349. doi: 10.1172/JCI121955.

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

Author information

1
Department of Immunology, Akita University Graduate School of Medicine, Akita, Japan.
2
Department of Vascular Molecular Physiology, Kanazawa University Graduate School of Medicine, Ishikawa, Japan.
3
Laboratory Animal Resource Center, University of Tsukuba, Ibaraki, Japan.

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.

KEYWORDS:

Angiogenesis; G-protein coupled receptors; endothelial cells

PMID:
31335323
PMCID:
PMC6763231
[Available on 2020-01-01]
DOI:
10.1172/JCI121955
Free full text

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation
Loading ...
Support Center