title: MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation.
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.
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, 300 George Street, 7th Floor, New Haven, Connecticut 06511, USA.
authors.forename: Irinna
authors.initials: I
authors.lastname: Papangeli
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, 300 George Street, 7th Floor, New Haven, Connecticut 06511, USA.|Department of Life Systems, Sookmyung Women's University, Seoul 140-742, Korea.
authors.forename: Jongmin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Roentgenstr. 20, 48149 Muenster, Germany.
authors.forename: Inna
authors.initials: I
authors.lastname: Maier
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, 300 George Street, 7th Floor, New Haven, Connecticut 06511, USA.
authors.forename: Saejeong
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Life Systems, Sookmyung Women's University, Seoul 140-742, Korea.
authors.forename: Aram
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, 300 George Street, 7th Floor, New Haven, Connecticut 06511, USA.
authors.forename: Yujung
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, 300 George Street, 7th Floor, New Haven, Connecticut 06511, USA.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Omar F
authors.identifier: http://orcid.org/0000-0003-3811-2369
authors.initials: OF
authors.lastname: Khan
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, 300 George Street, 7th Floor, New Haven, Connecticut 06511, USA.
authors.forename: Hyekyung
authors.initials: H
authors.lastname: Ju
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, 300 George Street, 7th Floor, New Haven, Connecticut 06511, USA.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: Department of Biological Sciences, Stanford University, Stanford, California 94305, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Red-Horse
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Roentgenstr. 20, 48149 Muenster, Germany.
authors.forename: Arndt F
authors.initials: AF
authors.lastname: Siekmann
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, 300 George Street, 7th Floor, New Haven, Connecticut 06511, USA.
authors.forename: Hyung J
authors.initials: HJ
authors.lastname: Chun
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D000069059:Atorvastatin / Q000494:pharmacology; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism; D018056:Hemorheology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D020239:Receptor Cross-Talk; D019718:Receptors, CXCR4 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012171:Retinal Vessels / Q000254:growth & development* / Q000378:metabolism*
chemical_list: D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C546202:MIRN139 microRNA, mouse; D035683:MicroRNAs; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled; D000069059:Atorvastatin