Deletion of endothelial cell endothelin B receptors does not affect blood pressure or sensitivity to salt.
Endothelin B receptors in different tissues regulate diverse physiological responses including vasoconstriction, vasodilatation, clearance of endothelin-1, and renal tubular sodium reabsorption. To examine the role of endothelial cell endothelin B receptors in these processes, we generated endothelial cell-specific endothelin B receptor knockout mice using a Cre-loxP approach. We have demonstrated loss of endothelial cell endothelin B receptor expression and function and preservation of nonendothelial endothelin B receptor-mediated responses through binding and functional assays. Ablation of endothelin B receptors exclusively from endothelial cells produces endothelial dysfunction in the absence of hypertension, with evidence of decreased endogenous release of NO and increased plasma endothelin-1. In contrast to models of total endothelin B receptor ablation, the blood pressure response to a high-salt diet is unchanged in endothelial cell-specific endothelin B receptor knockouts compared with control floxed mice. These findings suggest that the endothelial cell endothelin B receptor mediates a tonic vasodilator effect and that nonendothelial cell endothelin B receptors are important for the regulation of blood pressure.
Bagnall
Alan J
AJ
Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Little France Crescent, Edinburgh, EH16 4TJ United Kingdom. Alan.Bagnall@ed.ac.uk
Kelland
Nicholas F
NF
Gulliver-Sloan
Fiona
F
Davenport
Anthony P
AP
Gray
Gillian A
GA
Yanagisawa
Masashi
M
Webb
David J
DJ
Kotelevtsev
Yuri V
YV
D000367:Age Factors; D000818:Animals; D001011:Aorta; D001667:Binding, Competitive / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D019332:Endothelin-1 / Q000097:blood / Q000493:pharmacokinetics; D018390:Gene Targeting / Q000379:methods; D006579:Heterozygote; D006720:Homozygote; D006973:Hypertension / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D009924:Organ Culture Techniques; D044023:Receptor, Endothelin B / Q000235:genetics*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D014664:Vasodilation / Q000235:genetics
D019332:Endothelin-1; D044023:Receptor, Endothelin B; D017673:Sodium Chloride, Dietary; D009569:Nitric Oxide