Endothelin-1

Overview

Endothelin-1 (ET-1) was identified by Yanagisawa and colleagues in 1988 as a potent vasoconstrictor peptide secreted by cultured porcine aortic endothelial cells. It is the prototype member of the endothelin family, which also includes endothelin-2 (ET-2) and endothelin-3 (ET-3). ET-1 is produced by endothelial cells, smooth muscle cells, epithelial cells, and neurons. It acts as a paracrine and autocrine factor with diverse physiological roles beyond vasoconstriction.

Structure and Biosynthesis

ET-1 is a 21-amino acid peptide containing two intramolecular disulfide bonds (between Cys1-Cys15 and Cys3-Cys11), creating a bicyclic structure essential for receptor binding. The C-terminal tryptophan residue (Trp21) is critical for receptor activation.

The biosynthesis of ET-1 involves several proteolytic steps. Preproendothelin-1 (212 amino acids) is cleaved by furin-like proteases to form big endothelin-1 (38 amino acids), which is subsequently cleaved by endothelin-converting enzyme (ECE-1) at the Trp21-Val22 bond to yield the mature, biologically active ET-1. ECE-1 is a zinc metalloprotease located on the cell surface and in intracellular compartments.

Receptor System

ET-1 exerts its effects through two G-protein-coupled receptors:

• ETA receptors: Coupled to Gq and phospholipase C, mediating potent and sustained vasoconstriction through intracellular calcium mobilization and protein kinase C activation. ETA receptors are expressed on vascular smooth muscle cells, cardiac myocytes, and osteoblasts.
• ETB receptors: Expressed on endothelial cells, where they mediate vasodilation through nitric oxide and prostacyclin release, and on smooth muscle cells, where they contribute to vasoconstriction. ETB receptors also function as clearance receptors, internalizing circulating ET-1.

The balance between ETA and ETB receptor activation determines the net vascular response to ET-1.

Physiological Functions

ET-1 is a key regulator of basal vascular tone. It maintains tonic vasoconstriction and interacts with other vasoactive systems, including the renin-angiotensin-aldosterone system and sympathetic nervous system. Beyond hemodynamics, ET-1 promotes smooth muscle cell proliferation, cardiac hypertrophy, fibrosis, and inflammation. It also regulates epithelial cell function in the kidney and lung.

Pathophysiology and Therapeutics

Excessive ET-1 production or receptor signaling contributes to pulmonary arterial hypertension, systemic hypertension, heart failure, atherosclerosis, and chronic kidney disease. The endothelin receptor antagonists bosentan (dual ETA/ETB), ambrisentan (selective ETA), and macitentan (dual ETA/ETB) are approved for the treatment of pulmonary arterial hypertension, representing a clinically successful application of endothelin pathway pharmacology.