endothelina

Endothelin refers to a family of potent endothelium-derived vasoconstrictor peptides. In humans, endothelin-1 (ET-1) is the best characterized and is produced mainly by vascular endothelial cells. It is a 21-amino-acid peptide derived from the preproendothelin-1 gene EDN1, processed to big ET-1 and then cleaved by endothelin-converting enzymes to active ET-1. Two other isoforms, endothelin-2 (ET-2) and endothelin-3 (ET-3), are encoded by EDN2 and EDN3 and have tissue-specific distributions and roles, including development of neural crest–derived structures and gastrointestinal tissues.

Endothelins exert their effects through two G-protein-coupled receptors, ETA and ETB. ETA activation on vascular smooth muscle promotes vasoconstriction and cell proliferation; ETB receptors on endothelial cells stimulate nitric oxide and prostacyclin release leading to vasodilation, while ETB on smooth muscle can also mediate vasoconstriction. The net effect depends on receptor distribution and context. The endothelin system plays a central role in regulating vascular tone and blood pressure. It is also involved in pathophysiology of hypertension, heart failure, chronic kidney disease, and especially pulmonary arterial hypertension, where overactivation contributes to disease progression.

Therapeutic agents targeting the endothelin system, known as endothelin receptor antagonists (ERAs), are used clinically to treat PAH and certain other conditions. Examples include bosentan, ambrisentan, and macitentan. These drugs block ETA and/or ETB receptors and can improve exercise capacity and hemodynamics, though they require monitoring for hepatic safety and fluid retention. Research continues into the precise regulation of endothelin synthesis and receptor signaling as well as its role in other organ systems.