title: Aldosterone-Induced Vascular Remodeling and Endothelial Dysfunction Require Functional Angiotensin Type 1a Receptors.
abstract: We investigated the role of angiotensin type 1a receptors (AGTR1a) in vascular injury induced by aldosterone activation of mineralocorticoid receptors in Agtr1a(-/-) and wild-type (WT) mice infused with aldosterone for 14 days while receiving 1% NaCl in drinking water. Aldosterone increased systolic blood pressure (BP) by ≈30 mm Hg in WT mice and ≈50 mm Hg in Agtr1a(-/-) mice. Aldosterone induced aortic and small artery remodeling, impaired endothelium-dependent relaxation in WT mice, and enhanced fibronectin and collagen deposition and vascular inflammation. None of these vascular effects were observed in Agtr1a(-/-) mice. Aldosterone effects were prevented by the AGTR1 antagonist losartan in WT mice. In contrast to aldosterone, norepinephrine caused similar BP increase and mesenteric artery remodeling in WT and Agtr1a(-/-) mice. Agtr1a(-/-) mice infused with aldosterone did not increase sodium excretion in response to a sodium chloride challenge, suggesting that sodium retention could contribute to the exaggerated BP rise induced by aldosterone. Agtr1a(-/-) mice had decreased mesenteric artery expression of the calcium-activated potassium channel Kcnmb1, which may enhance myogenic tone and together with sodium retention, exacerbate BP responses to aldosterone/salt in Agtr1a(-/-) mice. We conclude that although aldosterone activation of mineralocorticoid receptors raises BP more in Agtr1a(-/-) mice, AGTR1a is required for mineralocorticoid receptor stimulation to induce vascular remodeling and inflammation and endothelial dysfunction.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada.|Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada.|Division of Nephrology (T.M.C.), Department of Medicine, Duke University, Durham, NC.
authors.forename: Marie
authors.initials: M
authors.lastname: Briet
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada.
authors.forename: Tlili
authors.initials: T
authors.lastname: Barhoumi
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada.
authors.forename: Muhammad Oneeb Rehman
authors.initials: MOR
authors.lastname: Mian
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada.
authors.forename: Suellen C
authors.initials: SC
authors.lastname: Coelho
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada.
authors.forename: Sofiane
authors.initials: S
authors.lastname: Ouerd
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Rautureau
authors.affiliation: Division of Nephrology (T.M.C.), Department of Medicine, Duke University, Durham, NC.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada.|Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, PQ, Canada.
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009638:Norepinephrine / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012016:Reference Values; D066253:Vascular Remodeling / Q000187:drug effects* / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D019808:Losartan; D009638:Norepinephrine
keywords: inflammation; mineralocorticoids; oxidative stress; potassium channels, calcium-activated; sodium; vascular remodeling