Vascular endothelin receptor type B: Structure, function and dysregulation in vascular disease

Endothelin-1 (ET-1) is a major regulator of vascular function, acting via both endothelin receptor type A (ETAR) and type B (ETBR). Although the role of ETAR in vascular smooth muscle (VSM) contraction has been studied, little is known about ETBR. ETBR is a G-protein coupled receptor with a molecular mass of ∼50 kDa and 442 amino acids arranged in seven transmembrane domains. Alternative splice variants of ETBR and heterodimerization and cross-talk with ETAR may affect the receptor function. ETBR has been identified in numerous blood vessels with substantial effects in the systemic, renal, pulmonary, coronary and cerebral circulation. ETBR in the endothelium mediates the release of relaxing factors such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor, and could also play a role in ET-1 clearance. ETBR in VSM mediates increases in [Ca2+]i, protein kinase C, mitogen-activated protein kinase and other pathways of VSM contraction and cell growth. ET-1/ETAR signaling has been associated with salt-sensitive hypertension (HTN) and pulmonary arterial hypertension (PAH), and ETAR antagonists have shown some benefits in these conditions. In search for other pathogenetic factors and more effective approaches, the role of alterations in endothelial ETBR and VSM ETBR in vascular dysfunction, and the potential benefits of modulators of ETBR in treatment of HTN and PAH are being examined. Combined ETAR/ETBR antagonists could be more efficacious in the management of conditions involving upregulation of ETAR and ETBR in VSM. Combined ETAR antagonist with ETBR agonist may need to be evaluated in conditions associated with decreased endothelial ETBR expression/activity.

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