Endothelin-1 and Its Receptors

Endothelin-1 (EDN1) is the most potent vasoconstrictor peptide identified to date, produced primarily by vascular endothelial cells. Its actions are mediated through two receptor subtypes:

ETA Receptors: Located mainly on vascular smooth muscle cells, ETA receptors promote sustained vasoconstriction, smooth muscle proliferation, and fibrosis. Overactivation of ETA contributes significantly to the pathological vascular remodeling seen in PAH.

ETB Receptors: Expressed on both endothelial and smooth muscle cells, ETB receptors have dual roles. On endothelial cells, they promote vasodilation via nitric oxide (NO) and prostacyclin release and facilitate clearance of circulating EDN1. Conversely, ETB receptors on smooth muscle cells can also mediate vasoconstriction.

The delicate balance between ETA and ETB signaling is disrupted in pulmonary hypertension, favoring sustained vasoconstriction, endothelial dysfunction, and abnormal cell growth.