| Endothelin 1 (ET‑1) is the principal isoform of the endothelin peptide family and a highly potent vasoconstrictor produced mainly by vascular endothelial cells, where it acts as an autocrine and paracrine regulator of vascular tone, cardiac load, and local tissue perfusion. The peptide is generated from a larger preproendothelin precursor that is processed by a furin-type convertase to big ET‑1, which is then cleaved by endothelin-converting enzyme or via a chymase–neprilysin route to yield the mature active peptide, providing several regulated processing steps that shape spatial and temporal ET‑1 production along the vascular wall and in organs such as the kidney, lung, and heart. The mature ET‑1 peptide binds two G protein‑coupled receptors, ETA and ETB, with ETA located predominantly on vascular smooth muscle cells and ETB present on both endothelium and smooth muscle, and receptor activation primarily couples to Gq/11 to stimulate phospholipase C, inositol 1,4,5‑trisphosphate generation, and Ca²⁺ mobilization, leading to sustained smooth muscle contraction and changes in arterial and venous resistance. ET‑1 receptor signaling also engages additional pathways, including epidermal growth factor receptor transactivation, Rho‑kinase activation, induction of oxidative stress, and modulation of adenylate cyclase activity, which extend ET‑1 effects to vascular remodeling, cell proliferation, extracellular matrix production, and alterations in myocardial and vascular muscle calcium handling. ETA-mediated signaling in resistance arteries and pulmonary vessels drives slow-onset, long-lasting vasoconstriction that depends mainly on Ca²⁺ influx through receptor- and store-operated channels and, to a lesser extent, on intracellular store release, while ETB receptors on endothelium promote nitric oxide and prostacyclin release that counterbalance constriction, illustrating how receptor distribution determines the net functional outcome of ET‑1 in a given vascular bed. ET‑1 production responds to hemodynamic and humoral inputs such as shear stress, hypoxia, angiotensin II, vasopressin, catecholamines, growth factors, and inflammatory cytokines, and is negatively regulated by endothelial nitric oxide, cGMP, and natriuretic peptides, which together integrate ET‑1 into broader networks controlling vascular homeostasis and fluid–electrolyte balance. Elevated ET‑1 levels and enhanced ETA/ETB signaling are characteristic of systemic hypertension, pulmonary arterial hypertension, heart failure, and atherosclerotic vascular disease, where ET‑1 contributes to increased vascular resistance, medial hypertrophy, adventitial fibrosis, endothelial dysfunction, and inflammatory activation. ET‑1 also promotes proliferation and matrix production in vascular smooth muscle cells and fibroblasts and stimulates profibrotic mediators such as IL‑11 in lung fibroblasts, linking this peptide to structural remodeling in pulmonary vasculature and interstitial compartments and to disease processes that include PAH, chronic lung disease, and cardiac remodeling. |
