title: The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure.
abstract: The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22α promoter (SM22α-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Cre-positive (SM22α)CaSR(Δflox/Δflox) [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca(2+)) concentrations (1-5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-l-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca(2+) concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR.
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom;
authors.forename: M
authors.initials: M
authors.lastname: Schepelmann
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom;
authors.forename: P L
authors.initials: PL
authors.lastname: Yarova
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom; Faculty of Pharmacy, Université de Picardie Jules Verne, Amiens, France;
authors.forename: I
authors.initials: I
authors.lastname: Lopez-Fernandez
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom;
authors.forename: T S
authors.initials: TS
authors.lastname: Davies
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom;
authors.forename: S C
authors.initials: SC
authors.lastname: Brennan
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom;
authors.forename: P J
authors.initials: PJ
authors.lastname: Edwards
authors.affiliation: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria;
authors.forename: A
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom; Pathology Sciences, AstraZeneca, Macclesfield, Cheshire, United Kingdom;
authors.forename: J
authors.initials: J
authors.lastname: Graça
authors.affiliation: Faculty of Science, Department for Life, Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom;
authors.forename: K
authors.initials: K
authors.lastname: Rietdorf
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark;
authors.forename: V
authors.initials: V
authors.lastname: Matchkov
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark;
authors.forename: R A
authors.initials: RA
authors.lastname: Fenton
authors.affiliation: Endocrine Research Unit, Department of Veteran Affairs Medical Center, Department of Medicine, University of California, San Francisco, Califonia;
authors.forename: W
authors.initials: W
authors.lastname: Chang
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria;
authors.forename: M
authors.initials: M
authors.lastname: Krssak
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom;
authors.forename: A
authors.initials: A
authors.lastname: Stewart
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Division of Pharmacology, Cardiff University, Cardiff, United Kingdom;
authors.forename: K J
authors.initials: KJ
authors.lastname: Broadley
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; and.
authors.forename: D T
authors.initials: DT
authors.lastname: Ward
authors.affiliation: Pathology Sciences, AstraZeneca, Macclesfield, Cheshire, United Kingdom;
authors.forename: S A
authors.initials: SA
authors.lastname: Price
authors.affiliation: Cardiff University, Wales Heart Research Institute, Cardiff, United Kingdom.
authors.forename: D H
authors.initials: DH
authors.lastname: Edwards
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom;
authors.forename: P J
authors.initials: PJ
authors.lastname: Kemp
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom; Riccardi@cf.ac.uk SchepelmannM@cf.ac.uk.
authors.forename: D
authors.initials: D
authors.lastname: Riccardi
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D001919:Bradycardia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D006339:Heart Rate; D007022:Hypotension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008638:Mesenteric Arteries / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology; D020257:Ventricular Remodeling
chemical_list: C577923:CASR protein, mouse; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D002118:Calcium
keywords: CaSR; G protein-coupled receptor; blood pressure regulation; blood vessel tone regulation; calcium-sensing receptor; vascular smooth muscle cells