Coronary Artery Development: Progenitor Cells and Differentiation Pathways

Abstract

Coronary artery disease (CAD) is the number one cause of death worldwide and involves the accumulation of plaques within the artery wall that can occlude blood flow to the heart and cause myocardial infarction. The high mortality associated with CAD makes the development of medical interventions that repair and replace diseased arteries a high priority for the cardiovascular research community. Advancements in arterial regenerative medicine could benefit from a detailed understanding of coronary artery development during embryogenesis and of how these pathways might be reignited during disease. Recent research has advanced our knowledge on how the coronary vasculature is built and revealed unexpected features of progenitor cell deployment that may have implications for organogenesis in general. Here, we highlight these recent findings and discuss how they set the stage to interrogate developmental pathways during injury and disease.

Keywords: blood flow; coronary artery; endocardium; sinus venosus; vascular remodeling.

Figure 1

Structure and cellular components of the coronary vasculature. (a) Schematic of the developmental events leading to mature coronary arteries. First, a coronary plexus (purple) covered in pericytes (yellow) migrates over the surface of the heart and into the myocardium. Then, plexus vessels attach to the aorta to initiate blood flow, triggering arterial remodeling (red) that ultimately leads to mature arteries. Panel adapted from Reference . (b) Illustration of the prominent cell types comprising the coronary vasculature.

Figure 2

Multiple progenitor cells contribute to the mature coronary vasculature in a region-specific manner. (a) Schematic of the sinus venosus and endocardium progenitor contributions to vessel components in different regions of the heart ventricle. Endothelial cells are indicated by continuous lines, and mural cells (pericytes and smooth muscle) and their progenitors are indicated by dashed lines. Progenitor sources are color-coded and arteries are denoted with an “A.” The heart ventricle is schematized as a box and the different heart regions are indicated below. (b) Schematic of the molecular pathways regulating different aspects of progenitor cell differentiation and morphogenesis during coronary development. The majority of the vascular endothelium arises through sprouting angiogenesis from the sinus venosus (solid blue lines) and endocardium (solid orange lines), guided by the molecules listed in blue or orange, respectively. The resulting immature vascular plexus migrates into the aorta forming a coronary artery stem, or ostia, under the guidance of the indicated factors. Following aortic attachment, a subset of the vascular plexus remodels into arteries, whose proper size is regulated by the growth factors and signaling pathways listed. During this process, the coronary endothelium is covered with pericytes that differentiate from both the epicardium (blue dashed circles) and cushion endocardium (orange dashed arrow). Both of these sources can produce coronary artery smooth muscle, and the epicardium does so through a pericyte intermediate (black curved arrow). Preotic neural crest also contributes to coronary artery smooth muscle (green arrow), primarily in the ventricular septum. The epicardium also differentiates into fibroblasts (blue circles) in a pathway distinct from that producing coronary mural cells (pericytes and smooth muscle), and this cell fate decision is made at the heart surface. Note that for simplicity the schematics in this figure do not include epicardial-derived endothelial cells, which represent a minor and less well-studied population. Abbreviations: BmpER, BMP binding endothelial regulator; CMC, cardiomyocyte; EndoMT, endocardium to mesenchymal transformation; Fgf, fibroblast growth factor; Mrtf, myocardin-related transcription factor; Pdgfrα, platelet-derived growth factor receptor alpha; Pdgfrβ, platelet-derived growth factor receptor beta; Vegf, vascular endothelial growth factor.