Published online before print May 3, 2007, doi: 10.1161/01.RES.0000269183.13937.e8
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Submitted on January 16, 2007
Revised on April 16, 2007
Accepted on April 25, 2007
Direct Evidence of Endothelial Oxidative Stress With Aging in Humans. Relation to Impaired Endothelium-Dependent Dilation and Upregulation of Nuclear Factor 
B
Anthony J. Donato *;
From the Department of Integrative Physiology, University of Colorado, Boulder.
* To whom correspondence should be addressed. E-mail: tony.donato{at}colorado.edu.
Aging is associated with impaired vascular endothelial function, as indicated in part by reduced endothelium-dependent dilation (EDD). Decreased EDD with aging is thought to be related to vascular endothelial cell oxidative stress, but direct evidence is lacking. We studied 95 healthy men: 51 young (23±1 years) and 44 older (63±1 years). EDD (brachial artery flow-mediated dilation) was 
50% lower in older versus young men (3.9±0.3% versus 7.6±0.3%, P<0.01; n=42 older/n=51 young). Abundance of nitrotyrosine (quantitative immunofluorescence), an oxidatively modified amino acid and marker of oxidative stress, was higher in endothelial cells (ECs) obtained from the brachial artery (1.25±0.12 versus 0.61±0.11 nitrotyrosine intensity/human umbilical vein EC [HUVEC] intensity, P=0.01; n=11 older/n=11 young) and antecubital veins (0.55±0.04 versus 0.34±0.03, P<0.05; n=19 older/n=17 young) of older men. Flow-mediated dilation was inversely related to arterial EC nitrotyrosine expression (r=-0.62, P=0.01; n=22). In venous samples, EC expression of the oxidant enzyme NAD(P)H oxidase-p47phox was higher in older men (0.71±0.05 versus 0.57±0.05 NAD[P]H oxidase-p47phox intensity/HUVEC intensity, P<0.05; n=19 older/n=18 young), whereas xanthine oxidase and the antioxidant enzymes cytosolic and mitochondrial superoxide dismutase and catalase were not different between groups. Nuclear factor 
B p65, a component of the redox-sensitive nuclear transcription factor nuclear factor B, was elevated in both arterial (P<0.05; n=9 older/n=12 young) and venous (P<0.01; n=13 older/n=15 young) EC samples of older men and correlated with nitrotyrosine expression (r=0.51, P<0.05 n=16). These results provide direct support for the hypothesis that endothelial oxidative stress develops with aging in healthy men and is related to reductions in EDD. Increased expression of NAD(P)H oxidase and nuclear factor B may contribute to endothelial oxidative stress with aging in humans.
Key words: flow-mediated dilation • NAD(P)H oxidase • xanthine oxidase • antioxidants
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