endoteliinin

Endothelin is a family of potent vasoconstrictor peptides that play a crucial role in regulating blood pressure, vascular tone, and cellular functions. The most well-studied member of this family is endothelin-1 (ET-1), a 21-amino acid peptide initially isolated from porcine aortic endothelial cells in 1988. It is synthesized primarily by endothelial cells lining blood vessels and is released in response to various stimuli, including hypoxia, shear stress, and inflammatory signals.

ET-1 exerts its effects by binding to two primary G-protein-coupled receptors: endothelin receptor type A (ETA) and endothelin receptor type B (ETB). ETA receptors are predominantly found on vascular smooth muscle cells and mediate vasoconstriction, while ETB receptors, found on both endothelial and smooth muscle cells, promote vasodilation through the release of nitric oxide and prostacyclin. ETB receptors also facilitate the clearance of ET-1 from circulation.

Beyond its role in vascular regulation, endothelin influences a wide range of physiological processes, including cell proliferation, migration, and apoptosis. Dysregulation of endothelin signaling has been implicated in various pathological conditions, such as hypertension, pulmonary hypertension, atherosclerosis, and heart failure. Elevated levels of ET-1 have been observed in diseases characterized by vascular remodeling and increased vascular resistance.

Endothelin also plays a role in non-vascular tissues, including the kidneys, where it regulates fluid balance and glomerular filtration rate, and in the central nervous system, where it influences neuronal activity and blood-brain barrier permeability. Therapeutic interventions targeting the endothelin system, such as endothelin receptor antagonists, have been developed to treat conditions like pulmonary arterial hypertension.

The synthesis of endothelin involves a multi-step process beginning with the precursor preproendothelin, which is cleaved into big endothelin. Big endothelin is then converted to the active ET-1 by endothelin-converting enzymes (ECEs), primarily ECE-1 and ECE-2. This enzymatic conversion is tightly regulated and can be modulated pharmacologically to influence endothelin levels.