Peripheral conduit artery flow-mediated dilatation decreases with ageing in humans. The underlying mechanisms and efficacy of preventive strategies are unknown. Brachial artery flow-mediated dilatation was determined at baseline and after ascorbic acid (vitamin C) intravenous infusion and chronic supplementation (500 mg day −1 for 30 days) in three groups of healthy men: young sedentary (n = 11; 25 ± 1 years, mean ± S.E.M.), older sedentary (n = 9; 64 ± 2), and older endurance-exercise trained (n = 9; 64 ± 2). At baseline, flow-mediated dilatation (normalized for the hyperaemic stimulus) was ∼45% lower in the older (0.015 ± 0.001) versus young (0.028 ± 0.004) sedentary men (P < 0.01), but was preserved in older exercising men (0.028 ± 0.004). Ascorbic acid infusion increased plasma concentrations > 15-fold in all groups and restored flow-mediated dilatation in the sedentary older men (to 0.023 ± 0.002; P > 0.1 versus other groups), with no effects in the other two groups. Oral ascorbic acid supplementation did not affect flow-mediated dilatation in any group. Brachial artery endothelium-independent dilatation (sublingual nitroglycerin) did not differ among the groups at baseline nor change with ascorbic acid administration. These results provide the first evidence for an important role of oxidative stress in both the impairment in peripheral conduit artery flow-mediated dilatation with sedentary human ageing and the preservation of flow-mediated dilatation with physically active ageing.

Brachial artery flow-mediated dilation (FMD) is impaired with aging and is associated with increased risk for cardiovascular disease (CVD). We determined if regular aerobic exercise improves brachial artery FMD in middle-aged/older (MA/O) men and postmenopausal women. In sedentary MA/O adults (age 55 – 79 years) without CVD, 8 weeks of brisk walking (6 days/week for ~50 min/day; randomized, controlled design) increased treadmill time ~20% in both MA/O men (n=11) and postmenopausal women (n=15) (P<0.01), without altering body composition or circulating CVD risk factors. Brachial artery FMD increased > 50% in the MA/O men (4.6 ± 0.6 to 7.1 ± 0.6%, P < 0.01), but did not change in the postmenopausal women (5.1 ± 0.8 vs. 5.4 ± 0.7%, P = 0.50). No changes occurred in the non-exercising controls. In a separate cross-sectional study (n =167), brachial artery FMD was ~50% greater in endurance exercise-trained (6.4 ± 0.4%, n = 45) vs. sedentary (4.3 ± 0.3%, n = 60) MA/O men (P < 0.001), whereas there were no differences between endurance-trained (5.3 ± 0.7%, n = 20) and sedentary (5.6 ± 0.5%, n = 42) postmenopausal women (P = 0.70). Brachial artery lumen diameter, peak hyperemic shear rate and endothelium independent dilation did not differ with exercise intervention or in the endurance-exercise vs. sedentary groups. Regular aerobic exercise is consistently associated with enhanced brachial artery FMD in MA/O men, but not in postmenopausal women. Some postmenopausal women without CVD may be less responsive to habitual aerobic exercise than MA/O men.

To determine whether impaired endothelium-dependent dilation (EDD) in older adults is associated with changes in the expression of major vasoconstrictor or vasodilator proteins in the vascular endothelium, endothelial cells (EC) were obtained from the brachial artery and peripheral veins of 56 healthy men, aged 18-78 yr. Brachial artery EC endothelin-1 (ET-1) [0.99 +/- 0.10 vs. 0.57 +/- 0.10 ET-1/human umbilical vein EC (HUVEC) intensity, P = 0.01] and serine 1177 phosphorylated endothelial nitric oxide synthase (PeNOS) (0.77 +/- 0.09 vs. 0.44 +/- 0.07 PeNOS/HUVEC intensity, P < 0.05) (quantitative immunofluorescence) were greater, and EDD (peak forearm blood flow to intrabrachial acetylcholine) was lower (10.2 +/- 0.9 vs. 14.7 +/- 1.7 ml.100 ml(-1).min(-1), P < 0.05) in older (n = 18, 62 +/- 1 yr) vs. young (n = 15, 21 +/- 1 yr) healthy men. EDD was inversely related to expression of ET-1 (r = -0.39, P < 0.05). Brachial artery EC eNOS expression did not differ significantly with age, but tended to be greater in the older men (young: 0.23 +/- 0.03 vs. older: 0.33 +/- 0.07 eNOS/HUVEC intensity, P = 0.08). In the sample with venous EC collections, EDD (brachial artery flow-mediated dilation) was lower (3.50 +/- 0.44 vs. 7.68 +/- 0.43%, P < 0.001), EC ET-1 and PeNOS were greater (P< 0.05), and EC eNOS was not different in older (n = 23, 62 +/- 1 yr) vs. young (n = 27, 22 +/- 1 yr) men. EDD was inversely related to venous EC ET-1 (r = -0.37, P < 0.05). ET-1 receptor A inhibition with BQ-123 restored 60% of the age-related impairment in carotid artery dilation to acetylcholine in B6D2F1 mice (5-7 mo, n = 8; 30 mo, n = 11; P < 0.05). ET-1 expression is increased in vascular EC of healthy older men and is related to reduced EDD, whereas ET-1 receptor A signaling tonically suppresses EDD in old mice. Neither eNOS nor PeNOS is reduced with aging. Changes in ET-1 expression and bioactivity, but not eNOS, contribute to vascular endothelial dysfunction with aging.

In experimental animals chronic elevations in arterial blood flow increase the lumen diameter and reduce the intima‐media thickness (IMT) of the arterial segment involved. We determined whether intermittent elevations in active muscle blood flow associated with regular aerobic leg exercise induced such expansive arterial remodelling in the common femoral artery of humans. In the cross‐sectional study 53 sedentary (47 ± 2 years) and 55 endurance exercise‐trained (47 ± 2 years) men were studied. Common femoral artery lumen diameter (B‐mode ultrasound) was 7 % greater (9.62 ± 0.12 vs. 9.03 ± 0.13 mm), and femoral IMT (0.46 ± 0.02 vs. 0.55 ± 0.02 mm) and IMT/lumen ratio were 16‐21 % smaller in the endurance‐trained men (all P < 0.001). Basal femoral artery blood flow (duplex ultrasound) was not different, shear stress tended to be lower (P = 0.08), and mean femoral tangential wall stress was 30 % higher in the endurance‐trained men (P < 0.001). In the intervention study 22 men (51 ± 2 years) were studied before and after 3 months of regular aerobic leg exercise (primarily walking). After training, the femoral diameter increased by 9 % (8.82 ± 0.18 vs. 9.60 ± 0.20 mm), and IMT (0.65 ± 0.05 vs. 0.56 ± 0.05 mm) and the IMT/lumen ratio were ≈15‐20 % smaller (all P < 0.001). Basal femoral blood flow and shear stress were not different after training, whereas the mean femoral tangential wall stress increased by 31 %. The changes in arterial structure were not related to changes in risk factors for atherosclerosis. Our results are consistent with the concept that regular aerobic leg exercise induces expansive arterial remodelling in the femoral artery of healthy men. This adaptive process is produced by even a moderate training stimulus, is not obviously dependent on corresponding improvements in risk factors for atherosclerosis, and is robust, occurring in healthy men of different ages.