Wei Ke, Díaz-Trelles Ramon, Liu Qiaozhen, Diez-Cuñado Marta, Scimia Maria-Cecilia, Cai Wenqing, Sawada Junko, Komatsu Masanobu, Boyle Joseph J, Zhou Bin, Ruiz-Lozano Pilar, Mercola Mark
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.
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Cardiovasc Res. 2015 Jul 15;107(2):287-94. doi: 10.1093/cvr/cvv167. Epub 2015 Jun 8.
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.
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.
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.
年龄和损伤会导致冠状动脉平滑肌细胞（caSMCs）发生结构和功能变化，这些变化会影响冠状动脉疾病的发病机制。尽管人们普遍认为旁分泌信号传导会驱动caSMCs的表型变化，但我们在此表明，胎儿心外膜内的发育起源也可能产生深远影响。
小鼠中的荧光染料和转基因脉冲标记技术显示，大多数caSMCs源自E12.5之前迁移的Wt1(+)、Gata5-Cre(+)细胞，而少数细胞源自较晚迁出且Wt1(+)、Gata5-Cre(-)的群体。我们通过对Rbpj进行Gata5-Cre切除来功能性评估早期迁出细胞对冠状动脉发育和疾病的影响，这会阻止它们对冠状动脉平滑肌细胞的贡献。Gata5-Cre(+)群体的消融导致冠状动脉仅由Gata5-Cre(-)的caSMCs组成。这些冠状动脉在成年早期看起来正常；然而，到5至8个月大时，它们逐渐纤维化，失去外膜外层弹性蛋白层，功能失调且渗漏，动物出现早期死亡。
综上所述，这些数据揭示了胎儿心外膜中与冠状动脉完整性相关的异质性，并且冠状动脉心外膜起源的扭曲易引发成年期疾病。
