title: Developmental origin of age-related coronary artery disease.
abstract: OBJECTIVE
  Age and injury cause structural and functional changes in coronary artery smooth muscle cells (caSMCs) that influence the pathogenesis of coronary artery disease. Although paracrine signalling is widely believed to drive phenotypic changes in caSMCs, here we show that developmental origin within the fetal epicardium can have a profound effect as well.
  
  
  RESULTS
  Fluorescent dye and transgene pulse-labelling techniques in mice revealed that the majority of caSMCs are derived from Wt1(+), Gata5-Cre(+) cells that migrate before E12.5, whereas a minority of cells are derived from a later-emigrating, Wt1(+), Gata5-Cre(-) population. We functionally evaluated the influence of early emigrating cells on coronary artery development and disease by Gata5-Cre excision of Rbpj, which prevents their contribution to coronary artery smooth muscle cells. Ablation of the Gata5-Cre(+) population resulted in coronary arteries consisting solely of Gata5-Cre(-) caSMCs. These coronary arteries appeared normal into early adulthood; however, by 5-8 months of age, they became progressively fibrotic, lost the adventitial outer elastin layer, were dysfunctional and leaky, and animals showed early mortality.
  
  
  CONCLUSIONS
  Taken together, these data reveal heterogeneity in the fetal epicardium that is linked to coronary artery integrity, and that distortion of the coronaries epicardial origin predisposes to adult onset disease.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92037, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Wei
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92037, USA.
authors.forename: Ramon
authors.initials: R
authors.lastname: Díaz-Trelles
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qiaozhen
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92037, USA Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Diez-Cuñado
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors.forename: Maria-Cecilia
authors.initials: MC
authors.lastname: Scimia
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92037, USA.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Cai
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Sawada
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Imperial Centre for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Boyle
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305, USA prlozano@stanford.edu mmercola@ucsd.edu.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ruiz-Lozano
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92037, USA prlozano@stanford.edu mmercola@ucsd.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Mercola
mesh_terms: D000375:Aging; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D003324:Coronary Artery Disease / Q000473:pathology*; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000196:embryology / Q000254:growth & development; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D010496:Pericardium / Q000196:embryology / Q000473:pathology*
keywords: Coronary artery disease; Epicardium; Pathology; Smooth muscle