title: Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors.
abstract: Hypertension is a cardiovascular risk factor present in over two-thirds of people over age 60 in North America; elevated blood pressure correlates with increased risk of heart attack, stroke and progression to heart and kidney failure. Current therapies are insufficient to control blood pressure in almost half of these patients. The mineralocorticoid receptor (MR), acting in the kidney, is known to regulate blood pressure through aldosterone binding and stimulation of sodium retention. However, recent studies support the concept that the MR also has extrarenal actions and that defects in sodium handling alone do not fully explain the development of hypertension and associated cardiovascular mortality. We and others have identified functional MR in human vascular smooth muscle cells (SMCs), suggesting that vascular MR might directly regulate blood pressure. Here we show that mice with SMC-specific deficiency of the MR have decreased blood pressure as they age without defects in renal sodium handling or vascular structure. Aged mice lacking MR in SMCs (SMC-MR) have reduced vascular myogenic tone, agonist-dependent contraction and expression and activity of L-type calcium channels. Moreover, SMC-MR contributes to angiotensin II–induced vascular oxidative stress, vascular contraction and hypertension. This study identifies a new role for vascular MR in blood pressure control and in vascular aging and supports the emerging hypothesis that vascular tone contributes directly to systemic blood pressure.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: McCurley
authors.forename: Paulo W
authors.initials: PW
authors.lastname: Pires
authors.forename: Shawn B
authors.initials: SB
authors.lastname: Bender
authors.forename: Mark
authors.initials: M
authors.lastname: Aronovitz
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Zhao
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hill
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dorrance
authors.forename: Michael E
authors.initials: ME
authors.lastname: Mendelsohn
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005697:Galactosides; D006321:Heart / Q000033:anatomy & histology; D007211:Indoles; D051379:Mice; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009929:Organ Size / Q000502:physiology; D016133:Polymerase Chain Reaction; D060888:Real-Time Polymerase Chain Reaction; D018161:Receptors, Mineralocorticoid / Q000172:deficiency / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D017931:DNA Primers; D005697:Galactosides; D007211:Indoles; D018161:Receptors, Mineralocorticoid; D012964:Sodium; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside