There has been tremendous progress over the past two decades elucidating general principles of blood vessel development and factors that control it1–4
, especially during tumor angiogenesis5,6
. Comparatively little is known, however, about the cellular origins and developmental programs of many of our most important vessels and vascular beds, such as the coronary arteries that supply the heart muscle (myocardium) and its pacemaker7–9
. Seven million people die each year of coronary artery disease and its sequealae, myocardial infarction and cardiac arrest, making it the leading cause of death worldwide10
. Tens of millions of others manage the disease medically or undergo major interventions such as angioplasty or coronary bypass surgery10
. Elucidating how coronary vessels arise during development and are maintained in adult life, and how they are remodeled under pathological conditions such as arteriosclerosis, should further our understanding of the disease. It could also lead to new treatments that stimulate vessel growth and new ways of engineering bypass grafts with the flow properties and durability of healthy young vessels.
The development of coronary arteries has been studied in a variety of animals for over a century. Early anatomical studies in humans and other mammals suggested that they bud from the aorta11–14
. More recent experiments with chick-quail chimeras argued against this and suggested instead that they arise from the proepicardium, a transitory structure in the embryo that contacts and spreads over the developing heart to form its epithelial covering (epicardium) and several internal tissues15–17
. The chick experiments and subsequent studies led to the current textbook view that coronary vessels form from proepicardial cells that undergo an epithelial-to-mesenchymal transition, and then differentiate into isolated endothelial progenitors that assemble de novo (“vasculogenesis”) into endothelial tubes7,18
. However, not all data from chick is easily reconciled with this model9,19
, and recent lineage tracing experiments in mouse show that, although the proepicardium gives rise to myocardial stroma and vascular smooth muscle, it gives rise to few, if any coronary endothelial cells20–23
. Thus, the origin of coronary artery endothelial cells, among the most medically important cells in the body, remains an enigma.
Here, we use histological and clonal analysis in mouse, and cardiac organ culture, to investigate the origins and early development of coronary arteries. The results show that coronary arteries do not derive from the proepicardium but from endothelial sprouts of the sinus venosus, the venous inflow tract of the embryonic heart, plus a small contribution from endocardium lining the cardiac chambers. The patterns of migration and marker expression of the venous sprouts suggest a model in which local signals in the developing heart induce angiogenic outgrowth, dedifferentiation, and stepwise conversion into coronary arteries, capillaries, and veins.