Coronary vessel assembly involves patterned endocardial sprouting and tip-cell-to artery specification

Abstract

The coronary vasculature comprises superficial coronary veins and deeper coronary arteries and capillaries that critically support the high metabolic activity of the beating heart. Understanding how different endothelial progenitor sources jointly shape and remodel the coronary vasculature into its adult pattern has recently attracted great research interest, and spurred much debate. Here, using lineage tracing tools in combination with three-dimensional imaging, live-imaging in explants and single-cell transcriptional profiling, we demonstrate that sprouting angiogenesis drives both sinus venosus and endocardial contribution to coronary plexus. Whereas previous studies limit endocardial contribution to coronary vessels to the interventricular septum and ventral aspect of the heart, our study demonstrates extensive endocardial sprouting angiogenesis in the free ventricular walls. In particular, we identify a distinct subpopulation of endocardial cells that express future coronary markers and reside in both the embryonic and adult ventricular wall endocardium. Most importantly, we provide evidence for sprouting angiogenesis from both endocardium and subepicardial plexus towards the inner myocardial wall to determine pre-arterial specification. Additionally, sprouting from the endocardium leads to the establishment of perfused connections to the advancing coronary plexus, also followed by transitioning to the pre-arterial cell state. Distinct molecular profiles characterize sprouting populations in the intramyocardial and subepicardial layers that shape the prospective coronary arteries and veins, respectively. Harnessing the endocardial progenitors and targeting the distinct sprouting populations may in the future serve to tailor cardiac vascular adaptations for therapeutic purposes.