Endothelin-1

Endothelin-1 (ET-1) is a 21-amino acid peptide produced primarily by vascular endothelial cells and is the most potent endogenous vasoconstrictor known. It plays critical roles in cardiovascular regulation, pulmonary hypertension pathophysiology, and renal function. Endothelin receptor antagonists (ERAs) such as bosentan and macitentan are FDA-approved treatments for pulmonary arterial hypertension, validating ET-1 as a key therapeutic target.

ET-1 is synthesized as a 212-amino acid preproendothelin, cleaved to Big Endothelin-1 (38 AA), then converted to the active 21-AA form by endothelin-converting enzyme (ECE). ET-1 acts on two GPCRs: ETA receptors (predominant on smooth muscle, mediating potent vasoconstriction and proliferation) and ETB receptors (on endothelial cells, mediating transient vasodilation via NO and prostacyclin release; also on smooth muscle mediating contraction). ETA activation is the dominant net effect, producing sustained vasoconstriction via PLC/IP3/DAG signaling and calcium mobilization.

ET-1 is implicated in pulmonary arterial hypertension, systemic hypertension, heart failure, renal disease, and preeclampsia. Multiple FDA-approved ERA drugs (bosentan, ambrisentan, macitentan) demonstrate the therapeutic importance of blocking ET-1 signaling. Research continues on ET-1's role in cancer progression, fibrosis, and neuropathic pain. ET-1 is used as a tool compound to model vascular disease in preclinical studies.