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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/H1914    most recent 00300.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Modrick, M. L. Articles by Faraci, F. M. PubMed PubMed Citation Articles by Modrick, M. L. Articles by Faraci, F. M.

Role of oxidative stress and AT₁ receptors in cerebral vascular dysfunction with aging

Departments of ¹Internal Medicine, ²Physiology, and ³Pharmacology, Cardiovascular Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa

Submitted 26 March 2009 ; accepted in final form 19 April 2009

Vascular dysfunction occurs with aging. We hypothesized that oxidative stress and ANG II [acting via ANG II type 1 (AT₁) receptors] promotes cerebral vascular dysfunction with aging. We studied young (5–6 mo), old (17–19 mo), and very old (23 ± 1 mo) mice. In basilar arteries in vitro, acetylcholine (an endothelium-dependent agonist) produced dilation in young wild-type mice that was reduced by 60 and 90% (P < 0.05) in old and very old mice, respectively. Similar effects were seen using A23187 [GenBank] , a second endothelium-dependent agonist. The vascular response to acetylcholine in very old mice was almost completely restored with tempol (a scavenger of superoxide) and partly restored by PJ34, an inhibitor of poly(ADP-ribose) polymerase (PARP). We used mice deficient in Mn-SOD (Mn-SOD^+/–) to test whether this form of SOD protected during aging but found that age-induced endothelial dysfunction was not altered by Mn-SOD deficiency. Cerebral vascular responses were similar in young mice lacking AT₁ receptors (AT₁^–/–) and wild-type mice. Vascular responses to acetylcholine and A23187 [GenBank] were reduced by 50% in old wild-type mice (P < 0.05) but were normal in old AT₁-deficient mice. Thus, aging produces marked endothelial dysfunction in the cerebral artery that is mediated by ROS, may involve the activation of PARP, but was not enhanced by Mn-SOD deficiency. Our findings suggest a novel and fundamental role for ANG II and AT₁ receptors in age-induced vascular dysfunction.

basilar artery; endothelium; genetically altered mice; acetylcholine; angiotensin II; A23187