title: Sex differences in angiotensin II responses contribute to a differential regulation of cox-mediated vascular dysfunction during aging.
abstract: Aging is a cardiovascular risk factor partially related to activation of the Renin-Angiotensin System (RAS). RAS activation is also influenced by sex. In this regard, our study aims to determine whether sex-associated differences in RAS contribute to a differential regulation of vascular aging and associated dysfunction. Male and female outbreed CD-1 mice were studied at 3 and 12months of age (M). Contribution of RAS was determined by treating mice from 3M to 12M with the AngII type 1 receptor blocker losartan (0.6g/L in the drinking water). At 12M, contractions to AngII were higher in males compared to females (P<0.05). This effect was paralleled by a decrease in AngII type 2 receptors in 12M males. Aging also diminished ACh relaxation in males, but did not modify female responses. Treatment of aortas with indomethacin (10μM) restored the impaired endothelium-dependent relaxation in 12M males, suggesting an increase of cyclooxygenase (COX)-derived vasoconstrictors in aged males. Chronic treatment of mice with losartan also improved endothelium-dependent relaxation. Besides, losartan significantly decreased COX-2 expression and activity in 12M male, with a minor effect in aged females. Aging increases AngII contraction and induces endothelial dysfunction differently in males and females. In aged males, RAS contributed to increased COX-2 expression and activity, which in turn may lead to vascular dysfunction.
authors.affiliation: Experimental Cardiology, Institut Clínic Cardiovascular, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Facultat de Medicina, Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Costa
authors.affiliation: Experimental Cardiology, Institut Clínic Cardiovascular, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Garabito
authors.affiliation: Facultat de Medicina, Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Jiménez-Altayó
authors.affiliation: Facultat de Medicina, Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Yara
authors.initials: Y
authors.lastname: Onetti
authors.affiliation: Experimental Cardiology, Institut Clínic Cardiovascular, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Sabate
authors.affiliation: Facultat de Medicina, Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vila
authors.affiliation: Experimental Cardiology, Institut Clínic Cardiovascular, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. Electronic address: adantas@clinic.ub.es.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Dantas
mesh_terms: D000375:Aging / Q000502:physiology*; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011453:Prostaglandins / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012737:Sex Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D011453:Prostaglandins; D000804:Angiotensin II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019808:Losartan; D007213:Indomethacin
keywords: Endothelial dysfunction; Prostaglandin; Renin-angiotensin system; Sex-differences; Vascular aging