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Title: Role of the endothelin B receptor in cardiovascular homeostasis
Author: Bagnall, Alan
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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The aim of this project was to precisely determine the role of the endothelial cell (EC) ETB receptor in the regulation of vascular tone, blood pressure and clearance of ET-1. Cre-loxP recombination was utilised to conditionally regulate ETB receptor expression in vivo. Mice featuring loxP sites flanking exons 2 and 3 of the ETB receptor gene (floxed ETB receptor mice) were generated by standard gene targeting techniques in embryonic stem cells. Floxed ETB mice were crossed with Tie2-Cre transgenic mice to produce mice in which recombination-mediated removal of ETB receptor coding regions was limited to EC (Flox/Flox Tie2). EC ETB receptor binding of 125I ET-1 and in vitro aortic and tracheal ring myography were performed to assess endothelial function and the response to selective ETB receptor agonists. Pulmonary EC ET-1 binding was decreased by ~80% in EC-specific ETB receptor knockout mice (cpm/50μg membrane protein ± SEM; Flox/Flox Tie2 581 ± 67; W/W -/- 3175 ± 268; n=3; p<0.001). Cell-specificity of ETB receptor down-regulation was demonstrated by maintenance of normal ETB receptor-mediated tracheal constriction. Blood pressure was increased in Flox/Flox Tie2 mice (MAP 137.2 ± 6.4mmHg (n=5); W/W -/-, 113.7 ± 4.7mmHg (n=6; p<0.05) but was not affected by dietary salt. Plasma ET-1 was increased ~4 fold following EC ETB receptor down-regulation (mean plasma [ET-1] pg/ml ± SEM; Flox/Flox Tie2 12.40 ± 2.95; W/W -/- 2.94 ± 0.83; n=6; p<0.001). Aortic rings from Flox/Flox Tie2 mice demonstrated impaired endothelium-dependant vasodilatation to ETB receptor selective agonists and acetylcholine but normal endothelium-independent vasodilatation. Recombination-mediated removal of exons 2 and 3 of the ETB receptor is sufficient to prevent expression of functional ETB receptors. The ‘floxed’ ETB receptor mouse thereby facilitates the cell type-specific down-regulation of ETB receptor expression in vivo. The EC ETB receptor plays an important role in the determination of blood pressure under normal physiological conditions. The mechanism underlying this effect may involve loss of EC ETB receptor-mediated vasodilatation or impaired clearance of ET-1 with a consequent increase in ETA receptor activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available