Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging.
Vascular dysfunction occurs with aging. We hypothesized that oxidative stress and ANG II [acting via ANG II type 1 (AT(1)) 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 approximately 60 and 90% (P < 0.05) in old and very old mice, respectively. Similar effects were seen using A23187, 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 AT(1) receptors (AT(1)(-/-)) and wild-type mice. Vascular responses to acetylcholine and A23187 were reduced by approximately 50% in old wild-type mice (P < 0.05) but were normal in old AT(1)-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 AT(1) receptors in age-induced vascular dysfunction.
Modrick
Mary L
ML
Department of Internal Medicine, Carver College of Medicine, University of Iowa, E318-2 GH, Iowa City, IA 52242-1081, USA.
Didion
Sean P
SP
Sigmund
Curt D
CD
Faraci
Frank M
FM
D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology; D000001:Calcimycin / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D007476:Ionophores; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D014665:Vasodilator Agents; D000804:Angiotensin II; D000001:Calcimycin; D013482:Superoxide Dismutase; D000109:Acetylcholine