Developmental origin of age-related coronary artery disease

Ke Wei, Ramon Díaz-Trelles, Qiaozhen Liu, Marta Diez-Cuñado, Maria Cecilia Scimia, Wenqing Cai, Junko Sawada, Masanobu Komatsu, Joseph J. Boyle, Bin Zhou, Pilar Ruiz-Lozano, Mark Mercola

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)287-294
Number of pages8
JournalCardiovascular research
Volume107
Issue number2
DOIs
StatePublished - Jul 15 2015
Externally publishedYes

Keywords

  • Coronary artery disease
  • Epicardium
  • Pathology
  • Smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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