Ke Wei1, Ramon Díaz-Trelles1, Qiaozhen Liu2, Marta Diez-Cuñado3, Maria-Cecilia Scimia4, Wenqing Cai1, Junko Sawada4, Masanobu Komatsu4, Joseph J Boyle5, Bin Zhou2, Pilar Ruiz-Lozano6, Mark Mercola7. 1. 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. 2. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. 3. 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. 4. 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. 5. Imperial Centre for Translational and Experimental Medicine, Imperial College London, Hammersmith Hospital, London, UK. 6. Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305, USA prlozano@stanford.edu mmercola@ucsd.edu. 7. 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.
Abstract
AIM: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIM: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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