Developmental origin of age-related coronary artery disease

K Wei, R Díaz-Trelles, Q Liu… - Cardiovascular …, 2015 - academic.oup.com
K Wei, R Díaz-Trelles, Q Liu, M Diez-Cunado, MC Scimia, W Cai, J Sawada, M Komatsu
Cardiovascular research, 2015academic.oup.com
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-Cr e+ cells that migrate …
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.
Oxford University Press