Pericytes are progenitors for coronary artery smooth muscle

Abstract

Epicardial cells on the heart’s surface give rise to coronary artery smooth muscle cells (caSMCs) located deep in the myocardium. However, the differentiation steps between epicardial cells and caSMCs are unknown as are the final maturation signals at coronary arteries. Here, we use clonal analysis and lineage tracing to show that caSMCs derive from pericytes, mural cells associated with microvessels, and that these cells are present in adults. During development following the onset of blood flow, pericytes at arterial remodeling sites upregulate Notch3 while endothelial cells express Jagged-1. Deletion of Notch3 disrupts caSMC differentiation. Our data support a model wherein epicardial-derived pericytes populate the entire coronary microvasculature, but differentiate into caSMCs at arterial remodeling zones in response to Notch signaling. Our data are the first demonstration that pericytes are progenitors for smooth muscle, and their presence in adult hearts reveals a new potential cell type for targeting during cardiovascular disease.The heart is a complex organ composed of several different cell types. Muscle cells of walls of the heart contract to pump blood around the body. These muscle cells are themselves supplied with blood from the coronary arteries that penetrate deep into this muscle tissue. The lining of the coronary arteries is made of endothelial cells, while smooth muscle cells (or SMCs for short) surround the arteries and provide support. The SMCs can also contract to increase or decrease blood flow to the heart, depending on the heart rate.Endothelial cells and SMCs of the coronary arteries physically interact but develop from different precursor cells. The coronary artery SMCs are derived from cells that comprise the outer layer of the heart (called the epicardium) and move inwards during embryonic development. However, it was not clear exactly what kind of cells these precursor cells are, or which molecular signals trigger their conversion into SMCs.Volz et al. have studied cardiac development in mice and used fluorescent labels to observed individual cells of the epicardium as they divided and moved. This revealed that when epicardial cells developed into the coronary artery SMCs, there was always an intermediate cell type that wrapped around the developing blood vessels. Upon further investigation, Volz et al. found that these cells were so-called pericytes, which otherwise support small blood vessels throughout the body. Furthermore, the pericytes that did not develop into SMCs remained near the coronary arteries and were still present in adult hearts. Lastly, experiments showed that a protein called Notch-3 is expressed on pericytes and interacts with another protein called Jagged-1 on endothelial cells to prompt the conversion of pericytes into SMCs.Since heart development is similar in mice and humans, these findings may have implications for future therapies of coronary artery disease, the most common cause of death worldwide. Currently there are no methods to trigger the formation of new coronary arteries after injury or blockage, but knowledge of the pericyte precursors and the signaling pathways that turn them into SMCs could eventually lead to new treatments.