New insights into the developmental mechanisms of coronary vessels and epicardium.

During heart development, the epicardium, which originates from the proepicardial organ (PE), is a source of coronary vessels. The PE develops from the posterior visceral mesoderm of the pericardial coelom after stimulation with a combination of weak bone morphogenetic protein and strong fibroblast growth factor (FGF) signaling. PE-derived cells migrate across the heart surface to form the epicardial sheet, which subsequently seeds multipotent subepicardial mesenchymal cells via epithelial-mesenchymal transition, which is regulated by several signaling pathways including retinoic acid, FGF, sonic hedgehog, Wnt, transforming growth factor-β, and platelet-derived growth factor. Subepicardial endothelial progenitors eventually generate the coronary vascular plexus, which acquires an arterial or venous phenotype, connects with the sinus venosus and aortic sinuses, and then matures through the recruitment of vascular smooth muscle cells under the regulation of complex growth factor signaling pathways. These developmental programs might be activated in the adult heart after injury and play a role in the regeneration/repair of the myocardium.