Analysis of the expression of genes encoding the endothelin signaling pathway in fetal, healthy and diseased adult human heart using single-cell transcriptomics.

This study maps the cellular landscape of the principal genes (EDN1, EDN2, EDN3, EDNRA, EDNRB, ECE1, and ECE2) in the endothelin signaling pathway using published single cell/nucleus RNA sequencing data, comparing cellular expression in healthy fetal, healthy adult, or diseased adult human hearts. EDN1 was the most abundantly expressed gene, principally localized to endothelial cells from all three conditions. EDN2 and EDN3 expression was only detectable in epicardial mesothelial cells forming the outer layer of the heart, important for cardiac development. EDNRA was expressed in contractile cells (cardiomyocytes and mural cells) with highest levels in pericytes, that are emerging as key regulators of coronary microvascular blood flow. EDNRB localized principally to all endothelial cells, with remarkably the highest expression in fetal Schwann cells of the peripheral nervous system. ECE1 was also present in all endothelial cells from adult and fetal hearts, with detectable levels in pericytes, vascular smooth muscle cells, fibroblasts and adipocytes, while ECE2 expression was sparse. There was pronounced upregulation of ECE1 in pericytes and other mural cells in myocardial ischemia. Our strategy combining databases highlights conserved and divergent expression patterns, particularly upregulation of ECE1 in ischemic mural cells, thereby uncovering a potential unexploited target for pharmaceutical intervention.