Endothelin

 Endothelin is a family of potent vasoconstrictor peptides, primarily produced by endothelial cells lining blood vessels. The three isoforms—endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3)—are encoded by separate genes. ET-1 is the most extensively studied and is recognized for its critical role in regulating vascular tone, blood pressure, and tissue homeostasis. ET-1 exerts its effects by binding to two G-protein-coupled receptors: ETA and ETB. ETA receptors are primarily located on vascular smooth muscle cells and mediate vasoconstriction and cell proliferation, while ETB receptors, found on endothelial cells, can induce both vasodilation (via nitric oxide and prostacyclin release) and vasoconstriction, depending on the physiological context.

Research has established endothelin's involvement in various cardiovascular diseases. Elevated ET-1 levels are associated with endothelial dysfunction, a hallmark of hypertension, atherosclerosis, and heart failure. In pulmonary arterial hypertension (PAH), ET-1 contributes to vascular remodeling and increased pulmonary vascular resistance. Endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, and macitentan, are clinically approved to treat PAH by blocking the detrimental effects of ET-1. These drugs have shown efficacy in improving exercise capacity and delaying disease progression.

Beyond cardiovascular diseases, endothelin plays a role in kidney function and fibrosis. In chronic kidney disease (CKD), ET-1 promotes inflammation, fibrosis, and glomerular injury, making it a potential therapeutic target. Additionally, endothelin has been implicated in cancer progression, where it enhances tumor growth, angiogenesis, and metastasis. ET-1 is overexpressed in various cancers, including prostate, ovarian, and breast cancer, and its inhibition has shown promise in preclinical studies.

Despite its pathological roles, endothelin is essential for normal vascular development and function. It regulates blood flow distribution, tissue perfusion, and wound healing. The dual nature of endothelin—both protective and harmful—underscores the importance of precise regulation in maintaining physiological balance. Ongoing research aims to develop targeted therapies that modulate endothelin signaling without disrupting its beneficial functions.