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

Abstract

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.

Increased Cerebrovascular Sensitivity to Endothelin-1 in a Rat Model of Obstructive Sleep Apnea: A Role for Endothelin Receptor B

“…These data suggest that increased cerebrovascular ET-1-mediated constrictions after OSA involves increased ROCK-mediated Ca 2+ sensitization ( Figure 7) and are consistent with the previous studies showing that activation of G 12/13 protein by ET B R enhances Ca 2+ sensitivity through ROCK. 7 In conclusion, we show that OSA significantly alters the constrictor response of cerebral arteries to ET-1. We observe increased ET-1 sensitivity in the absence of elevated BP or upregulation of key components of the ET-1/ET-1 receptor system.…”

“…16 It should be noted that ET B R has been shown to signal through G q11,12 and 13 , which are involved in the activation of both TRPCs and ROCK. 7,34,35 Given that inhibition of either TRPCs or ROCK alone fully restored vascular contractility to sham levels, we propose that these mechanisms may act in series. Although further investigation is required, ROCK has been shown to activate TRPCs.…”

“…Endothelin-1 and its signaling pathways are often upregulated during pathologic states. 7,[19][20][21][22] For these studies, we used our recently developed rat model of OSA. 6 We report three major findings from this study.…”

Intracellular Endothelin Type B Receptor-driven Ca2+ Signal Elicits Nitric Oxide Production in Endothelial Cells

“…Based on these findings, we cannot exclude the participation of both types of Ca 2ϩ pools. Moreover, we found that the phospholipase C inhibitor U-73122 abolished the effect of ET-1; this is not surprising, given that ET B receptors couple to G q/11 (11) and that phospholipase C is present in the lysosomal membrane (51 (52,53) and endothelial NO synthase phosphorylation (54), which leads to the release of the vasorelaxant mediator NO. Indeed, intracellular administration of ET-1 resulted in NO release, an effect that was completely contingent on endothelial NO synthase.…”

“…Accordingly, various types of receptors, including GPCRs, have been reported to trigger signal transduction pathways upon their endolysosomal activation (1,47). However, the ET-1 binding pocket on the ET B receptor is located on the N-terminal side, thus within the lysosomal lumen (11). We have previously demonstrated that angiotensin II is transferred inside the endolysosomal vesicles via microautophagy (17), a process in which soluble cytosolic molecules are engulfed (48).…”