title: Role of smooth muscle cell mineralocorticoid receptor in vascular tone.
abstract: Identification of the mineralocorticoid receptor (MR) in the vasculature (i.e., endothelial and smooth muscle cells) raised the question of its role in vascular function and blood pressure control. Using a mouse model with conditional inactivation of MR in vascular smooth muscle cell (VSMC) (MR(SMKO)), we have recently shown that the VSMC MR is crucial for aldosterone-salt-induced carotid stiffening. In the present study, we have investigated the specific contribution of the VSMC MR in the regulation of vascular tone in large vessels. In MR(SMKO) mice, contractions induced by potassium chloride and calcium (Ca(2+)) are decreased in the aorta, whereas contraction is normal in response to phenylephrine and caffeine. The difference in response to Ca(2+) suggests that the VSMC-specific deficiency of the MR modifies VSM Ca(2+) signaling but without altering the intracellular Ca(2+) store handling. The relaxation induced by acetylcholine is not affected by the absence of MR. However, the relaxation induced by Ach in the presence of indomethacin and the relaxation induced by sodium nitroprussiate are significantly reduced in MR(SMKO) mice compared to controls. Since endothelial nitric oxide synthase (eNOS) activity is increased in mutant mice, their altered relaxation reflects impairment of the nitric oxide (NO) signaling pathway. In addition to altered NO and Ca(2+) signaling, the activity of myosin light chain and its regulators, myosin light chain kinase (MLCK) and myosin phosphatase (MLCP), is reduced. In conclusion, MR expressed in VSMC is required for NO and Ca(2+) signaling pathways and contractile protein activity leading to an altered contraction/relaxation coupling.
authors.affiliation: Centre de Recherche des Cordeliers, Inserm U1138 Team 1, 15 rue de l'Ecole de Medecine, Paris Cedex 06, 75270, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Tarjus
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Belozertseva
authors.forename: Huguette
authors.initials: H
authors.lastname: Louis
authors.forename: Soumaya
authors.initials: S
authors.lastname: El Moghrabi
authors.forename: Carlos
authors.initials: C
authors.lastname: Labat
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacolley
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jaisser
authors.forename: Guillaume
authors.initials: G
authors.lastname: Galmiche
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D056966:Excitation Contraction Coupling; D066298:In Vitro Techniques; D008297:Male; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D018161:Receptors, Mineralocorticoid; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D009219:Myosin-Light-Chain Kinase; D043263:Myosin-Light-Chain Phosphatase