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 Ϯ 1 mo) mice. In basilar arteries in vitro, acetylcholine (an endothelium-dependent agonist) produced dilation in young wild-type mice that was reduced by ϳ60 and 90% (P Ͻ 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 ϩ/Ϫ ) 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 (AT1 Ϫ/Ϫ ) and wild-type mice. Vascular responses to acetylcholine and A23187 were reduced by ϳ50% in old wild-type mice (P Ͻ 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 ageinduced vascular dysfunction. basilar artery; endothelium; genetically altered mice; acetylcholine; angiotensin II; A23187

Beneficial effects of lifelong caloric restriction on endothelial function are greater in conduit arteries compared to cerebral resistance arteries

“…This is in accordance with previous results reported by us and others Csiszar et al 2007a;Blackwell et al 2004;Modrick et al 2009;Hatake et al 1990). Lifelong CR completely prevented this age-related decline in EDD in conduit arteries (carotid), but only partially prevents the decline in cerebral resistance arteries (MCA).…”

“…Although we cannot compare absolute differences in the amount of superoxide production between arteries due (Miller et al 2005(Miller et al , 2009. Similar to previous studies, we find that scavenging superoxide improves EDD in conduit and cerebral arteries from old mice (Blackwell et al 2004;Lesniewski et al 2009;Mayhan et al 2008;Modrick et al 2009) and does not affect EDD in conduit arteries from young or old CR mice (Csiszar et al 2009). However, we demonstrate that scavenging superoxide in the MCA from young and old CR mice results in reduced EDD, which is in accordance with previous studies demonstrating reactive oxygen species contribute to the dilation of resistance arteries in skeletal muscle (Sindler et al 2013;Trott et al 2011), cardiac muscle (Miura et al 2003;Feng et al 2010;Kang et al 2011), and cerebral tissue (Drouin et al 2007).…”

“…Older humans and rodents exhibit impaired EDD in conduit arteries as well as cerebral arteries Csiszar et al 2007a;Blackwell et al 2004;Modrick et al 2009;Hatake et al 1990;Eskurza et al 2004;Celermajer et al 1994). It has been shown previously that lifelong CR can prevent the age-related decline in EDD in the aorta (Csiszar et al 2009), but the effect of CR on resistance artery EDD has not been studied.…”

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

“…Previous investigations have revealed an association between upregulation of tissue renin-angiotensin system (RAS) and structural remodeling and functional impairments in large arteries of aged animals and humans (86,128,173,(212)(213)(214).…”

Aging and the Renin-Angiotensin System

“…38 Additional evidence indicates that the beneficial effect of ACEi or ARB in reducing heart, kidney, and brain damage associated with aging is attributed to the drug capacity to attenuate ROS production and preserve mitochondrial function. [39][40][41][42][43] Lending support to the role of various RAS components in oxidative injury predisposing to aging are findings that ACE2 null mice are more sensitive to Ang II-mediated oxidative stress and inflammation than wild-type littermates. 44 Moreover, overexpression of ACE2 in the central nervous system reduces oxidative stress and improves autonomic function in mice.…”