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

J Clin Invest. 2019 Jul 23;129(10):4332-4349. doi: 10.1172/JCI121955.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Calcium-Binding Proteins / metabolism*
  • Cell Cycle Proteins / metabolism*
  • Endothelial Cells / metabolism
  • Female
  • Gene Expression Regulation, Developmental*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lysophospholipids / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic*
  • Protein Domains
  • Receptors, Lysophosphatidic Acid / metabolism
  • Receptors, Notch / metabolism
  • Receptors, Purinergic / metabolism
  • Receptors, Purinergic P2 / metabolism
  • Retina / metabolism
  • Signal Transduction
  • Trans-Activators / metabolism*
  • beta Catenin / metabolism


  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • DLL4 protein, human
  • DLL4 protein, mouse
  • LPAR4 protein, human
  • Lpar4 protein, mouse
  • Lysophospholipids
  • Receptors, Lysophosphatidic Acid
  • Receptors, Notch
  • Receptors, Purinergic
  • Receptors, Purinergic P2
  • Trans-Activators
  • Wwtr1 protein, mouse
  • Yap1 protein, mouse
  • beta Catenin
  • lysophosphatidic acid

Grant support

to Satoshi Ishii