Epicardial-myocardial signaling directing coronary vasculogenesis

Abstract

The establishment of the coronary circulation is critical for the development of the embryonic heart. Over the last several years, there has been tremendous progress in elucidating the pathways that control coronary development. Interestingly, many of the pathways that regulate the development of the coronary vasculature are distinct from those governing vasculogenesis in the rest of the embryo. It is becoming increasingly clear that coronary development depends on a complex communication between the epicardium, the subepicardial mesenchyme, and the myocardium mediated in part by secreted growth factors. This communication coordinates the growth of the myocardium with the formation of the coronary vasculature. This review summarizes our present understanding of the role of these growth factors in the regulation of coronary development. Continued progress in this field holds the potential to lead to novel therapeutics for the treatment of patients with coronary artery disease.

Figure 1. Steps in Coronary Vascular Development

In (A), the epicardium is formed by migration of proepicardial cells (blue) to the surface of the heart tube (orange), forming an epithelial sheet. In (B), epithelial-to-mesenchymal transformation produces cells with hemangioblast (red), smooth muscle (green) and fibroblast (blue) cell fates. In (C), a primitive endothelial plexus forms from the endothelial progenitors, with venous-fated endothelial tubes (dark blue) forming subepicardially and arterial-fated endothelial tubules forming intramyocardially (red). In (D), the endothelial plexus remodels and recruits vascular smooth muscle and other adventitial cells to form the mature coronary arteries (red) and veins (dark blue).

Figure 2. Evidence for a Sub-epicardial Hemangioblast

Shown above is a transverse section of a wild-type embryonic day 12.5 heart at the level of the interventricular groove stained with hematoxylin and eosin. Arrows indicate red blood cell-filled lumens of the primitive endothelial plexus.

Figure 3. Epicardial-Myocardial Signaling Pathways in Coronary Vascular Development

Shown above is a schematic of the cross talk between the epicardium (blue) and myocardium (red) during the early stages of coronary development. An FGF-Shh-VEGF/Ang2 dependent pathway is important for the generation of coronary endothelial progenitors (right), while β-catenin, PDGF, TGFβ, and Thymosin β4 are important for the development of coronary vascular smooth muscle (left).