title: Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammation.
abstract: Vascular endothelial dysfunction occurs during the human aging process, and it is considered as a crucial event in the development of many vasculopathies. We investigated the underlying mechanisms of this process, particularly those related with oxidative stress and inflammation, in the vasculature of subjects aged 18-91 years without cardiovascular disease or risk factors. In isolated mesenteric microvessels from these subjects, an age-dependent impairment of the endothelium-dependent relaxations to bradykinin was observed. Similar results were observed by plethysmography in the forearm blood flow in response to acetylcholine. In microvessels from subjects aged less than 60 years, most of the bradykinin-induced relaxation was due to nitric oxide release while the rest was sensitive to cyclooxygenase (COX) blockade. In microvessels from subjects older than 60 years, this COX-derived vasodilatation was lost but a COX-derived vasoconstriction occurred. Evidence for age-related vascular oxidant and inflammatory environment was observed, which could be related to the development of endothelial dysfunction. Indeed, aged microvessels showed superoxide anions (O(2)(-)) and peroxynitrite (ONOO(-)) formation, enhancement of NADPH oxidase and inducible NO synthase expression. Pharmacological interference of COX, thromboxane A(2)/prostaglandin H(2) receptor, O(2)(-), ONOO(-), inducible NO synthase, and NADPH oxidase improved the age-related endothelial dysfunction. In situ vascular nuclear factor-kappaB activation was enhanced with age, which correlated with endothelial dysfunction. We conclude that the age-dependent endothelial dysfunction in human vessels is due to the combined effect of oxidative stress and vascular wall inflammation.
authors.affiliation: Unidad de Investigación, Hospital Universitario de Getafe, Madrid, Spain. lrodriguez.hugf@salud.madrid.org
authors.forename: Leocadio
authors.initials: L
authors.lastname: Rodríguez-Mañas
authors.forename: Mariam
authors.initials: M
authors.lastname: El-Assar
authors.forename: Susana
authors.initials: S
authors.lastname: Vallejo
authors.forename: Pedro
authors.initials: P
authors.lastname: López-Dóriga
authors.forename: Joaquin
authors.initials: J
authors.lastname: Solís
authors.forename: Roberto
authors.initials: R
authors.lastname: Petidier
authors.forename: Manuel
authors.initials: M
authors.lastname: Montes
authors.forename: Julián
authors.initials: J
authors.lastname: Nevado
authors.forename: Marta
authors.initials: M
authors.lastname: Castro
authors.forename: Carmen
authors.initials: C
authors.lastname: Gómez-Guerrero
authors.forename: Concepción
authors.initials: C
authors.lastname: Peiró
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Sánchez-Ferrer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000737:chemistry / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation
chemical_list: D018836:Inflammation Mediators; D016328:NF-kappa B; D013481:Superoxides; D009569:Nitric Oxide; D011451:Prostaglandin-Endoperoxide Synthases