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

Lysophosphatidic acid (LPA) is a potent lipid mediator with various biological functions mediated through six G proteincoupled receptors (GPCRs), LPA1-LPA6. Previous studies have demonstrated that LPA-G alpha 12/G alpha 13 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 G alpha 12/G alpha 13-Rho-ROCK signaling in ECs. YAP/TAZ knockdown increased endothelial expression of the Notch ligand delta-like ligand 4 (DLL4) that was mediated by beta-catenin and Notch intracellular domain (NICD). Fibrin gel sprouting assay revealed that LPA4/LPA6, G alpha 12/G alpha 13, 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 G alpha 12/G alpha 13-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.