EDN1 encodes endothelin-1 (ET-1), a potent 21-amino acid vasoconstrictor peptide synthesized primarily by vascular endothelial cells. ET-1 binds G protein-coupled receptors EDNRA and EDNRB, activating intracellular signaling cascades including PTK2B, BCAR1, BCAR3, and RhoA pathways in multiple cell types. In vascular smooth muscle, ET-1 promotes arterial wall remodeling through ROCK-mediated activation of NFATC3, driving smooth muscle hypertrophy and differentiation. Beyond vascular function, ET-1 is expressed in neurons of the spinal cord and dorsal root ganglia, suggesting roles in neural transmission and modulation 1. EDN1 dysfunction is implicated in multiple vascular and inflammatory diseases. The rs5370 polymorphism is associated with increased pulmonary arterial hypertension risk 2, and variants affecting EDN1 expression—such as the rs9349379 G allele—enhance circulating ET-1 concentrations and are enriched in microvascular angina 3. In cancer, ET-1 engages β-arrestin-1 to regulate extracellular matrix protein expression (type I collagen and fibronectin) in ovarian cancer-associated fibroblasts, with high EDN1 expression combined with elevated collagen or fibronectin predicting poor serous ovarian cancer prognosis 4. Recent evidence demonstrates that BMP9 drives PAH pathogenesis partly through endothelial EDN1 upregulation, positioning endothelin antagonism as a therapeutic strategy; clinical trials with the selective ET-A receptor antagonist zibotentan have been conducted, although short-term treatment showed limited efficacy in microvascular angina 3.