Ets1-regulated endothelial-secreted factors promote compact myocardial growth and contribute to the pathogenesis of ventricular non-compaction

Aims Thinning of the compact myocardium is a major contributor to adverse outcomes in ventricular non-compaction, the third most common form of cardiomyopathy. Endothelial-specific deletion of Ets1, a gene associated with Jacobsen syndrome, causes ventricular non-compaction with reduced compact myocardium. However, the mechanisms by which pathological cardiac endothelium impairs compact myocardium growth remain poorly understood. Methods and results To uncover the mechanisms underlying compact myocardium thinning and identify therapeutic endothelial-secreted factors, we performed single-cell RNA sequencing. Aberrant cardiomyocyte and endothelial cell states were observed in non-compacted ventricles. Conditional deletion of Ets1 in either the endocardium or coronary endothelium impaired compact myocardial growth. In endocardium, Ets1 deficiency suppressed Notch1 signaling by upregulating Dlk1 and downregulating Dll4, both direct Ets1 targets. In coronary endothelium, Ets1 deficiency reduced the expression of its direct targets Hmcn1, Slit2, and Col18a1, three extracellular matrix (ECM) components that promote compact myocardial proliferation. Notably, treatment with these ECM proteins or the Notch1 effector Nrg1 restored the impaired compact myocardial proliferation. Conclusions These findings highlight Ets1-regulated endothelial-secreted factors as essential for compact myocardium development and suggest novel therapeutic targets for ventricular non-compaction.