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

Abstract

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.

Fig. 1.

Baseline diameter (A) and changes in diameter of the basilar artery in response to KCl (50 mM; B) and papaverine (100 μM; C) in young (n = 10), old (n = 11), and very old (VO; n = 9) wild-type (WT; Mn-SOD^+/+) and Mn-SOD^+/− mice [knockout (KO); n = 7 young, 6 old, and 16 VO mice]. WT mice were littermates of Mn-SOD^+/− mice and were on a CD-1 genetic background (1). Values are means ± SE. *P < 0.05 vs. young WT mice; #P < 0.05 vs. young Mn-SOD^+/− mice.

Fig. 2.

Responses of the basilar artery to acetylcholine in young (n = 10), old (n = 11), and VO (n = 9) Mn-SOD^+/+ and Mn-SOD^+/− mice (n = 7 young, 6 old, and 16 VO mice). Responses in very old mice were examined in the absence and presence of tempol (T). Values are means ± SE. *P < 0.05 vs. young mice; †P < 0.05 vs. old mice; #P < 0.05 vs. VO mice.

Fig. 3.

Dilation of the basilar artery in response to A23187 in young and old Mn-SOD^+/+ and Mn-SOD^+/− mice. Values are means ± SE; n = 7 young WT and Mn-SOD^+/− mice and 6 old WT and Mn-SOD^+/− mice. *P < 0.05 vs. young mice.

Fig. 4.

Dilation of the basilar artery in response to acetylcholine and A23187 in young and old WT [ANG II type 1 receptor (AT₁)^+/+] and AT₁ receptor-deficient (AT₁^−/−) mice. WT mice were littermates of the AT₁ receptor-deficient mice and were on a mixed genetic background of 129P3/J and C57BL/6J (14).Values are means ± SE; n = 8 young and old WT mice and 9 young and old AT₁^−/− mice. *P < 0.05 vs. young mice.