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

Irinna Papangeli, Jongmin Kim, Inna Maier, Saejeong Park, Aram Lee, Yujung Kang, Keiichiro Tanaka, Omar F. Khan, Hyekyung Ju, Yoko Kojima, Kristy Red-Horse, Daniel G. Anderson, Arndt F. Siekmann and Hyung J. Chun ()
Additional contact information
Irinna Papangeli: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine
Jongmin Kim: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine
Inna Maier: Max Planck Institute for Molecular Biomedicine
Saejeong Park: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine
Aram Lee: Sookmyung Women’s University
Yujung Kang: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine
Keiichiro Tanaka: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine
Omar F. Khan: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Hyekyung Ju: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine
Yoko Kojima: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine
Kristy Red-Horse: Stanford University
Daniel G. Anderson: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Arndt F. Siekmann: Max Planck Institute for Molecular Biomedicine
Hyung J. Chun: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11268

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