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Updated: Mar 22, 2026
Analysis of Coronary Vessels in Cleared Embryonic Hearts
Published on: December 7, 2016
Endocardium Minimally Contributes to Coronary Endothelium in the Embryonic Ventricular Free Walls
Hui Zhang1, Wenjuan Pu1, Guang Li1
1From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences (H.Z., W.P., X.H., L.H., X.T., Q.L., L.Z., B.Z.) and Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences (B.Z.), Chinese Academy of Sciences, Shanghai, China; Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (G.L., S.M.W.); Broad CIRM Center and Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles (H.M.S.); and School of Life Science and Technology, ShanghaiTech University, Shanghai, China (B.Z.).
Insights
The sinus venosus (SV), not the endocardium, is the primary source of embryonic coronary endothelium. This finding resolves a long-standing debate on coronary vessel development and aids research into vessel formation and regeneration.
Area of Science:
- Cardiovascular Development
- Vascular Biology
- Embryology
Background:
- The developmental origin of coronary vessels remains uncertain, with proposed sources including ventricular endocardium and sinus venosus (SV).
- Distinguishing between these origins is crucial for understanding coronary vessel formation and its implications for therapeutic angiogenesis.
Purpose of the Study:
- To definitively resolve the controversy surrounding the developmental origin of coronary vessels.
- To identify specific markers for lineage tracing of endocardial and SV cells.
Main Methods:
- Utilized nuclear factor of activated T cells (Nfatc1)-Cre and Nfatc1-Dre lineage tracers.
- Performed single-cell gene expression analysis to identify novel endocardial markers, discovering natriuretic peptide receptor 3 (Npr3).
- Conducted genetic lineage tracing using Npr3-CreER and intersectional genetic lineage tracing experiments.
Main Results:
- Nfatc1 labeling identified both endocardial and SV endothelial cells, necessitating a more specific marker.
- Npr3 was identified as a specific marker for endocardium, absent in the SV.
- Npr3-CreER lineage tracing revealed minimal contribution of endocardium to embryonic coronary vessels in ventricular free walls.
Conclusions:
- The sinus venosus (SV) is the major origin of coronary endothelium in embryonic ventricular free walls.
- The endocardium contributes minimally to the coronary endothelium in these regions.
- This study resolves the controversy over coronary endothelium development, providing a foundation for future research on coronary vessel formation and regeneration.
Rationale:
There is persistent uncertainty regarding the developmental origins of coronary vessels, with 2 principal sources suggested as ventricular endocardium or sinus venosus (SV). These 2 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.
Objective:
To resolve the controversy over the developmental origin of coronary vessels.
Methods And Results:
We first generated nuclear factor of activated T cells (Nfatc1)-Cre and Nfatc1-Dre lineage 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 on Npr3-CreER showed 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.
Conclusions:
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.
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