Section Review Cardiovascular & Renal: Endothelin receptors and atherosclerosis: a potential target for therapeutic intervention

Abstract

Endothelin (ET) is a powerful vasoconstrictor that affects vascular tone and blood pressure; however, recent evidence suggests that ET acts as an autocrine or paracrine factor and plays a role in the pathogenesis of atherosclerosis. In humans and in animal models, elevated plasma ET concentrations are associated with hypercholesterolaemia and atherosclerosis. ET and its receptors are located in endothelial cells, macrophages and smooth muscle cells of atherosclerotic and arteriosclerotic lesions. In vitro, endothelial cells, macrophages and smooth muscle cells synthesise ET and express ET receptors. Oxidised low density lipoprotein (LDL), growth factors, vasoactive peptides, and cytokines induce ET gene expression and protein synthesis. Conversely ET stimulates the synthesis of growth factors, inflammatory mediators, chemokines and adhesion molecules. In animal models, ET receptor antagonists decrease fatty streak progression during hypercholesterolaemia, and inhibit the formation of a fibrous neointima following arterial balloon catheter injury. It appears likely that ET indirectly promotes several phases of atherogenesis such as monocyte diapedesis into the artery wall, and the migration and proliferation of vascular smooth muscle cells. In summary, ET appears to be intricately involved in the elaboration of paracrine and autocrine factors mediating inflammation and wound healing. Pharmacological blockade of ET receptors inhibits the development of vascular lesions as a result of either hypercholesterolaemia or physical injury. Thus, it is possible that ET receptor antagonists could be used therapeutically to treat human vascular diseases such as atherosclerosis.

Key Words:

• atherosclerosis
• chemokines
• cytokines
• endothelin
• endothelin receptor antagonists
• endothelin receptors
• growth factors
• macrophage
• smooth muscle cells