title: The CXCL12/CXCR4 Axis Plays a Critical Role in Coronary Artery Development.
abstract: The chemokine CXCL12 and its receptor CXCR4 have many functions during embryonic and post-natal life. We used murine models to investigate the role of CXCL12/CXCR4 signaling in cardiac development and found that embryonic Cxcl12-null hearts lacked intra-ventricular coronary arteries (CAs) and exhibited absent or misplaced CA stems. We traced the origin of this phenotype to defects in the early stages of CA stem formation. CA stems derive from the peritruncal plexus, an encircling capillary network that invades the wall of the developing aorta. We showed that CXCL12 is present at high levels in the outflow tract, while peritruncal endothelial cells (ECs) express CXCR4. In the absence of CXCL12, ECs were abnormally localized and impaired in their ability to anastomose with the aortic lumen. We propose that CXCL12 is required for connection of peritruncal plexus ECs to the aortic endothelium and thus plays a vital role in CA formation.
authors.affiliation: Developmental Biology of Birth Defects, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. Electronic address: s.ivins@ucl.ac.uk.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ivins
authors.affiliation: Developmental Biology of Birth Defects, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Joel
authors.initials: J
authors.lastname: Chappell
authors.affiliation: Developmental Biology of Birth Defects, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Vernay
authors.affiliation: Developmental Biology of Birth Defects, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Jenifer
authors.initials: J
authors.lastname: Suntharalingham
authors.affiliation: Developmental Biology Division, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Alexandrine
authors.initials: A
authors.lastname: Martineau
authors.affiliation: Developmental Biology Division, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mohun
authors.affiliation: Developmental Biology of Birth Defects, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology*; D003331:Coronary Vessels / Q000166:cytology / Q000196:embryology*; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D005260:Female; D006321:Heart / Q000502:physiology*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4