Endocardial Cells Form the Coronary Arteries by Angiogenesis through Myocardial-Endocardial VEGF Signaling

The origins and developmental mechanisms of coronary arteries are incompletely understood. We show here by fate mapping, clonal analysis, and immunohistochemistry that endocardial cells generate the endothelium of coronary arteries. Dye tracking, live imaging, and tissue transplantation also revealed that ventricular endocardial cells are not terminally differentiated; instead, they are angiogenic and form coronary endothelial networks. Myocardial Vegf-a or endocardial Vegfr-2 deletion inhibited coronary angiogenesis and arterial formation by ventricular endocardial cells. In contrast, lineage and knockout studies showed that endocardial cells make a small contribution to the coronary veins, the formation of which is independent of myocardial-to-endocardial Vegf signaling. Thus, contrary to the current view of a common source for the coronary vessels, our findings indicate that the coronary arteries and veins have distinct origins and are formed by different mechanisms. This information may help develop better cell therapies for coronary artery disease. [Display omitted] ► Ventricular endocardial cells are a major origin of the coronary arteries ► Ventricular endocardial cells generate coronary arteries by angiogenesis ► Myocardial Vegf-a to endocardial Vegfr-2 signaling regulates coronary angiogenesis ► The coronary arteries and veins arise largely from different origins and mechanisms Cells of the endocardium, the inner layer of the heart, give rise to coronary arteries in a process that involves Vegf signaling from the myocardium (heart muscle) to the endocardium. Surprisingly, Vegf signaling is not required for the formation of coronary veins, suggesting distinct origins for coronary arteries and veins.