Abstract

There is persistent uncertainty regarding the developmental origins of coronary vessels, with two principal sources suggested as ventricular endocardium or sinus venosus (SV). These two proposed origins implicate fundamentally distinct mechanisms of vessel formation. Resolution of this controversy is critical for deciphering the programs that result in the formation of coronary vessels, and has implications for research on therapeutic angiogenesis.To resolve the controversy over the developmental origin of coronary vessels.We first generatedNfatc1-CreandNfatc1-Drelineage tracers for endocardium labeling. We found that Nfatc1 recombinases also label a significant portion of SV endothelial cells in addition to endocardium. Therefore, restricted endocardial lineage tracing requires a specific marker that distinguishes endocardium from SV. By single cell gene expression analysis, we identified a novel endocardial gene natriuretic peptide receptor 3 (Npr3). Npr3 is expressed in the entirety of the endocardium but not in the SV. Genetic lineage tracing based onNpr3-CreERshowed that endocardium contributes to a minority of coronary vessels in the free walls of embryonic heart. Intersectional genetic lineage tracing experiments demonstrated that endocardium minimally contributes to coronary endothelium in the embryonic ventricular free walls.Our study suggested that SV, but not endocardium, is the major origin for coronary endothelium in the embryonic ventricular free walls. This work thus resolves the recent controversy over the developmental origin of coronary endothelium, providing the basis for studying coronary vessel formation and regeneration after injury.

View details for DOI 10.1161/CIRCRESAHA.116.308749

View details for Web of Science ID 000377885100009

View details for PubMedID 27056912