endothelin

Endothelin is a family of 21-amino-acid peptide vasoconstrictors produced mainly by vascular endothelium. The best known member is endothelin-1 (ET-1); two additional isoforms, ET-2 and ET-3, are expressed in various tissues with tissue-specific patterns. Endothelins are synthesized as preproendothelin-1, processed to big ET-1, and activated by endothelin-converting enzymes ECE-1 and ECE-2 to ET-1.

Endothelins mediate their effects by binding to two G protein–coupled receptors, ETA and ETB. ETA receptors are predominantly on vascular smooth muscle and trigger vasoconstriction and cell proliferation. ETB receptors are abundant on endothelial cells, where they promote the release of nitric oxide and prostacyclin leading to vasodilation; ETB receptors on smooth muscle can also contribute to vasoconstriction depending on context.

Physiologically, endothelin contributes to basal vascular tone and regional blood flow regulation and participates in renal and pulmonary vascular resistance, cardiac remodeling, and development. In disease, endothelin signaling is often upregulated, notably in pulmonary arterial hypertension, systemic hypertension, heart failure, and preeclampsia, contributing to vasoconstriction and remodeling of the vasculature.

Therapeutically, endothelin receptor antagonists are used to treat PAH, including bosentan (nonselective ETA/ETB), ambrisentan (selective ET_A), and macitentan (nonselective with favorable pharmacology). Potential adverse effects include liver function abnormalities, edema, and anemia; interactions with hepatic enzymes are important for dosing. Experimental approaches include inhibition of endothelin-converting enzymes.

Endothelin production is modulated by other endothelium-derived factors such as nitric oxide and prostacyclin, which oppose its vasoconstrictor actions. Circulating ET-1 levels can be measured, though routine measurement is not universally used outside research.