B6D2F1 Mice Are a Suitable Model of Oxidative Stress-Mediated Impaired Endothelium-Dependent Dilation With Aging

Abstract

To determine if B6D2F1 mice represent a suitable model of oxidative stress-mediated impaired endothelium-dependent dilation (EDD) with aging, mice were studied at 6.9 +/- 0.3 and 31.9 +/- 0.6 months. EDD to acetylcholine (ACh) was 26% (p < .001) and 12% (p < .001) lower, respectively, in isolated carotid (n = 10-11) and femoral (n = 10) arteries from older mice, and reductions in arterial pressure to systemic ACh infusion were smaller in older mice (n = 6-10; p < .01). Nitrotyrosine was marked in aorta of older mice (p < .05, n = 4). Superoxide production in carotid arteries was greater (p < .05), and TEMPOL restored dilation in carotid arteries and systemically in older mice. N(G)-nitro-l-arginine methyl ester (l-NAME) reduced carotid artery dilation in young more than older mice, whereas TEMPOL restored the effects of l-NAME in older mice. Carotid artery stiffness was increased in older compared with young mice (p = .04). Our results provide the first comprehensive evidence that B6D2F1 mice are a useful model for investigating mechanisms of reduced nitric oxide-dependent, oxidative stress-associated EDD and increased arterial stiffness with aging.

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

“…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).…”

The effects of resveratrol on aging vessels

“…Further, treatment with the SOD mimetic Tempol restored endothelium-dependent dilation, and prevented the formation of atheroma plaques (Cannizzo et al, 2014;Lesniewski et al, 2009;Tatchum-Talom and Martin, 2004). Taken together, these data corroborate the effect of free radicals, particularly O2-on the age-related endothelial dysfunction in humans and other animals.…”

TNF-α impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity

“…To assess endothelial function, arteries were excised, cleared of surrounding adipocytes, and cannulated in the stage of a pressure myograph (DMT). Arteries were preconstricted with 2 M phenylephrine, and EDD as well as the NO contribution to dilation was measured in response to the cumulative addition of Ach (1 ϫ 10 Ϫ9 to 1 ϫ 10 Ϫ4 mol/l) in the absence or presence of the NO synthase inhibitor N -nitro-L-arginine methyl ester (L-NAME) (0.1 mmol/l, 30 min), as described previously (10,21). To determine the effect of TNF-␣ on vasodilation, a second arterial segment from the same eWAT was incubated intraluminally with recombinant TNF-␣ (rTNF; 1 ng/ml; R&D Systems) or a neutralizing antibody against mouse TNF-␣ (abTNF; 20 g/ml; R&D Systems) for 1 h before performing the aforementioned ACh dose responses.…”

“…To determine the effect of TNF-␣ on vasodilation, a second arterial segment from the same eWAT was incubated intraluminally with recombinant TNF-␣ (rTNF; 1 ng/ml; R&D Systems) or a neutralizing antibody against mouse TNF-␣ (abTNF; 20 g/ml; R&D Systems) for 1 h before performing the aforementioned ACh dose responses. Endotheliumindependent dilation was assessed in response to sodium nitroprusside (SNP; 1 ϫ 10 Ϫ10 to 1 ϫ 10 Ϫ4 mol/l) (10,21). Vessel diameters were measured by MyoView software (DMT).…”

“…Here, we demonstrate that TNF-␣ impairs EDD and NO bioavailability in resistance arteries excised from the epididymal white adipose tissue (eWAT), a visceral adipose depot of lean mice, but this in vitro effect of TNF-␣ is absent in the arteries isolated from the inflamed adipose tissue of glucose-intolerant insulin-resistant HF-fed mice. (9,10,21).…”