Ets1-regulated endothelial-secreted factors promote compact myocardial growth and contribute to the pathogenesis of ventricular non-compaction.
Summary
Endothelial Ets1 orchestrates compact myocardial growth via Notch1 signaling and secretion of ECM factors. Conditional Ets1 deletion in endocardial or coronary endothelium impairs proliferation; exogenous Hmcn1, Slit2, Col18a1, or Notch1 effector Nrg1 restore growth, nominating targets for ventricular non-compaction.
Key Findings
- Single-cell RNA-seq revealed aberrant endothelial and cardiomyocyte states in non-compacted ventricles.
- Ets1 deletion in endocardium suppressed Notch1 signaling via Dlk1 upregulation and Dll4 downregulation.
- Ets1 deletion in coronary endothelium reduced Hmcn1, Slit2, and Col18a1, ECM components that promote proliferation.
- Exogenous ECM proteins or Notch1 effector Nrg1 restored compact myocardial proliferation.
Clinical Implications
Although preclinical, findings support exploring ECM protein delivery or Notch1/Nrg1 pathway modulation as therapeutic strategies for ventricular non-compaction.
Why It Matters
Provides mechanistic, targetable pathways linking endothelial biology to compact myocardium development and ventricular non-compaction, with rescue experiments supporting translational potential.
Limitations
- Preclinical models; human validation is lacking.
- Long-term safety and delivery strategies for ECM or Nrg1 therapies remain untested.
Future Directions
Validate Ets1-dependent targets in human ventricular non-compaction tissues; develop delivery systems for ECM/Nrg1; assess efficacy and safety in large-animal models.
Study Information
- Study Type
- Basic/mechanistic study
- Research Domain
- Pathophysiology
- Evidence Level
- IV - Preclinical mechanistic study using conditional knockouts and scRNA-seq with rescue experiments.
- Study Design
- OTHER