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

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Abstract
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, 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 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.