MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation

Nat Commun. 2016 Apr 12;7:11268. doi: 10.1038/ncomms11268.

Abstract

G protein-coupled receptor (GPCR) signalling, including that involving apelin (APLN) and its receptor APLNR, is known to be important in vascular development. How this ligand-receptor pair regulates the downstream signalling cascades in this context remains poorly understood. Here, we show that mice with Apln, Aplnr or endothelial-specific Aplnr deletion develop profound retinal vascular defects, which are at least in part due to dysregulated increase in endothelial CXCR4 expression. Endothelial CXCR4 is negatively regulated by miR-139-5p, whose transcription is in turn induced by laminar flow and APLN/APLNR signalling. Inhibition of miR-139-5p in vivo partially phenocopies the retinal vascular defects of APLN/APLNR deficiency. Pharmacological inhibition of CXCR4 signalling or augmentation of the miR-139-5p-CXCR4 axis can ameliorate the vascular phenotype of APLN/APLNR deficient state. Overall, we identify an important microRNA-mediated GPCR crosstalk, which plays a key role in vascular development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines / metabolism
  • Animals
  • Apelin
  • Apelin Receptors
  • Atorvastatin / pharmacology
  • Down-Regulation
  • Endothelial Cells / metabolism
  • Hemorheology
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Phenotype
  • Receptor Cross-Talk*
  • Receptors, CXCR4 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Retinal Vessels / growth & development*
  • Retinal Vessels / metabolism*

Substances

  • Adipokines
  • Apelin
  • Apelin Receptors
  • Apln protein, mouse
  • Aplnr protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • MIRN139 microRNA, mouse
  • MicroRNAs
  • Receptors, CXCR4
  • Receptors, G-Protein-Coupled
  • Atorvastatin