Vascular biology of endothelin

Endothelins (ETs) are 21-amino-acid peptides produced in many cells and tis sues. The vascular ET system is represented mainly by ET-1 produced in endo thelial cells. PreproET-1 gene expression is regulated by transactivating s ignals dependent on cooperative interaction of GATA-2 and AP-1 sites. ProET -1 is acted on by a furin-like enzyme to generate big ET-1, a 38-39-amino-a cid peptide, which is converted to the mature 21-amino-acid peptide ET-1 by ET-converting enzyme (ECE) in endothelial cells, both intracellularly and on the cell membrane, and on the surface of underlying smooth muscle cells. The mature peptide ET-1 acts in a paracrine manner on smooth muscle cell E TA and ETB receptors to induce contraction and growth, and in an autocrine or paracrine manner on endothelial cells to induce production of the vasore laxant and growth-inhibitory agents nitric oxide (NO) and prostacyclin. ET receptors are G-protein-coupled, resulting in activation of phospholipase C and generation of two second messengers, inositol triphosphate and diacylg lycerol, which respectively stimulate calcium release and protein kinase C activation. Phospholipase D activation with generation of diacylglycerol, p hospholipase A(2) stimulation with release of arachidonic acid, activation of the Na+/H+ exchanger, and activation of tyrosine kinases and MAP kinases , are other pathways that contribute to contraction and growth induced by E T receptor stimulation. ET receptors may be downregulated by ET, especially under conditions in which large amounts of ET are being produced in the va sculature. This has been demonstrated in some models of experimental hypert ension and in some forms of human hypertension. Some of the effects of angi otensin II, particularly growth of the smooth muscle media of blood vessels , have been shown under some conditions to be mediated by ET-1 via ETA rece ptors. Many ET-induced effects on smooth muscle cells can be blocked by ETA -selective ET antagonists, which makes possible an identification of the ph ysiologic and pathophysiologic roles of the ET system in cardiovascular dis eases such as hypertension, heart failure, atherosclerosis, coronary heart disease, restenosis after angioplasty, primary pulmonary hypertension, and other pahologic conditions.