title: Resistance artery remodeling in deoxycorticosterone acetate-salt hypertension is dependent on vascular inflammation: evidence from m-CSF-deficient mice.
abstract: Deoxycorticosterone acetate (DOCA)-salt hypertension has an important endothelin-1 (ET-1)-dependent component. ET-1-induced vascular damage may be mediated in part by oxidative stress and vascular inflammation. Homozygous osteopetrotic (Op/Op) mice, deficient in macrophage colony-stimulating factor (m-CSF), exhibit reduced inflammation. We investigated in osteopetrotic (Op/Op) mice the effects of DOCA-salt hypertension on vascular structure, function, and oxidative stress, the latter as manifested by reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase activity. Mice were implanted with DOCA (200 mg/mouse, under 5% isofluorane anesthesia) and given saline for 14 days. Systolic blood pressure (mmHg) was significantly increased (146 +/- 2 and 138 +/- 1; P < 0.001 vs. basal 115 +/- 3 and 115 +/- 3, respectively) by DOCA-salt in wild-type (+/+) and heterozygous (Op/+) mice, but not in Op/Op mice (130 +/- 1 vs. basal 125 +/- 3). Norepinephrine contractile response was significantly enhanced, while acetylcholine endothelium-dependent vasodilation was significantly impaired in DOCA-salt-treated +/+ and Op/+ mice compared with control mice. No changes in norepinephrine-induced contraction and acetylcholine-induced relaxation were observed in DOCA-salt Op/Op mice. DOCA-salt +/+ and Op/+ mice had significantly increased mesenteric resistance artery media-to-lumen ratio and media cross-sectional area, neither of which were altered in Op/Op mice. Basal vascular superoxide production and NAD(P)H oxidase activity, vascular cell adhesion molecule-1 expression, and macrophage infiltration were significantly increased only in DOCA-salt +/+ mice. Thus m-CSF-deficient mice developed less endothelial dysfunction, vascular remodeling, and oxidative stress induced by DOCA-salt than +/+ and Op/+ mice, suggesting that inflammation may play a role in DOCA-salt hypertension, a model that results in part from effects of ET-1, which has proinflammatory actions.
authors.affiliation: 1Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Eun A
authors.initials: EA
authors.lastname: Ko
authors.forename: Farhad
authors.initials: F
authors.lastname: Amiri
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Pandey
authors.forename: Danesh
authors.initials: D
authors.lastname: Javeshghani
authors.forename: Eyal
authors.initials: E
authors.lastname: Leibovitz
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000818:Animals; D015415:Biomarkers; D003900:Desoxycorticosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000276:immunology; D006973:Hypertension / Q000276:immunology / Q000503:physiopathology*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008638:Mesenteric Arteries / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D010022:Osteopetrosis / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D014657:Vasculitis / Q000276:immunology / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; D019332:Endothelin-1; D017382:Reactive Oxygen Species; D013481:Superoxides; D003900:Desoxycorticosterone; D016173:Macrophage Colony-Stimulating Factor