Endothelin, its diverse biological activities and mechanisms of action

Endothelin, originally identified as a vasoconstrictive peptide derived from vascular endothelial cells, is now known to exert diverse biological effects on a wide variety of tissues and cell types through its own receptor(s). One of the outstanding actions of endothelin is a cell growth promoting activity which is demonstrated in several cell types including cultured vascular smooth muscle cells, fibroblasts, glomerular mesangial cells and osteoblasts. The mitogenic effect is likely mediated by stimulation of phospholipase C via receptor-G-protein coupling, and subsequent activation of protein kinase C. The effect of endothelin may contribute to the cell-proliferation response under various physiological and pathological conditions, such as wound healing and development of atherosclerosis and glomerulonephritis. Recently, three distinct endothelin-related genes have been cloned, suggesting that mammals, including humans, produce three members of this peptide family, endothelin (ET)-1 (the 'classical' endothelin), ET-2 and ET-3, which may act on distinct subtypes of endothelin receptor to induce different cellular responses.