Endothelial cell-specific ET_B receptor knockout: autoradiographic and histological characterisation and crucial role in the clearance of endothelin-1This article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

Abstract

Inactivation of endothelin B receptors (ETB), either through selective pharmacological antagonism or genetic mutation, increases the circulating concentration of endothelin-1 (ET-1), suggesting ETB plays an important role in clearance of this peptide. However, the cellular site of ETB-mediated clearance has not yet been determined. We have used a novel mouse model of endothelial cell-specific knockout (KO) of ETB (EC ETB(-/-)) to evaluate the relative contribution of EC-ETB to the clearance of ET-1. Phenotypic evidence of EC-specific ETB KO was confirmed by immunocytochemistry and autoradiography. Binding of the radiolabelled selective ETB ligand BQ3020 was significantly and selectively decreased in EC-rich tissues of EC ETB(-/-) mice, including the lung, liver, and kidney. By contrast, ETA binding was unaltered. RT-PCR confirmed equal expression of ET-1 in tissue from EC ETB(-/-) mice and controls, despite increased concentration of plasma ET-1 in EC ETB(-/-). Clearance of an intravenous bolus of [(125)I]ET-1 was impaired in EC ETB(-/-) mice. Pretreatment with the selective ETB antagonist A192621 impaired [(125)I]ET-1 clearance in control animals to a similar extent, but did not further impair clearance in EC ETB(-/-) mice. These studies suggest that EC-ETB are largely responsible for the clearance of ET-1 from the circulation.

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives

“…Although the vasoconstriction associated with ET B antagonism could reflect, in part, diminished vasodilatory input, evidence indicates that this is not the principal mechanism. Pharmacological blockade or genetic ablation of ET B receptors results in increased circulating ET-1 (10,34,50,70), and the associated increases in blood pressure can be normalized by ET A antagonism (34), suggesting this hypertensive effect more likely reflects increased ET-1 activation of ET A receptors rather than a loss of tonic vasodilatory input. The resultant increase in circulating ET-1 following ET B receptor antagonism is consistent with the role of ET B receptors in mediating systemic clearance of ET-1 (50).…”

Downregulation of Microvascular Endothelial Type B Endothelin Receptor Is a Central Vascular Mechanism in Hypertensive Pregnancy

“…ET A R is mainly expressed in vascular smooth muscle (VSM) to induce vasoconstriction, whereas ET B R is predominately expressed in endothelial cells to induce the release of vasodilator substances, 14,15 and also plays a role in ET-1 clearance. 16 Although a role of ET-1 and its vasoconstrictor ET A R in modulation of cardiovascular-renal function during HTN-Preg has been suggested, 3,17-19 the role of vasodilator endothelial ET B R during Norm-Preg and HTN-Preg, and the post-ET B R mediators involved are less clear.…”

Highly Selective Endothelin-1 Receptor A Inhibition Prevents Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice

“…Since many fibrotic features appear to be promoted by ETA receptors [33,35,36], we tested the effect of highly selective ETA receptor blockade in BLM-induced murine lung inflammation and fibrosis. Although nonselective ET-1 receptor inhibition improves the BLM lesion in rodents, there is a theoretical advantage to preserving ETB receptor signaling [11][12][13], since endothelial ETB receptor promotes vasodilatory and anti-inflammatory actions and clears ET-1 from the pulmonary circulation [37,38]. Despite encouraging preclinical results, however, several randomized control trials using nonselective or modestly selective ETA receptor antagonists in IPF patients showed no benefit [39][40][41][42].…”