Kerrie L. Moreau

Greater Age-Related Reductions in Central Arterial Compliance in Resistance-Trained Men

Reductions in the compliance of central arteries exert a number of adverse effects on systemic cardiovascular function and disease risk. Using the cross-sectional study design, we determined the relation between chronic resistance training and carotid arterial compliance. A total of 62 healthy normotensive men, 20 to 39 years of age (young) and 40 to 60 years of age (middle-aged), who were either sedentary or resistance-trained, were studied. In both activity groups, carotid arterial compliance (simultaneous ultrasound and applanation tonometry) was lower ( P P P r =−0.35; P

Regular exercise, hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women

OBJECTIVE Carotid arterial compliance is reduced with age in sedentary estrogen-deficient women, contributing to the development of cardiovascular disorders. We determined the effects of regular aerobic exercise, hormone replacement therapy (HRT), and their interaction on carotid arterial compliance using a combination of cross-sectional and intervention study designs. METHODS Cross-sectionally, we studied three groups of healthy postmenopausal women (50-80 years): 20 sedentary not taking HRT; 24 sedentary taking HRT; and 14 endurance-trained not taking HRT; and 11 sedentary premenopausal controls (20-37 years). In the intervention study, 12 sedentary postmenopausal women (58+/-3 years) who were taking HRT were studied before and after participation in a 3-month aerobic exercise (walking) program. Carotid arterial compliance was measured via simultaneous common carotid artery ultrasound imaging and applanation tonometry. RESULTS Cross-sectional study. Carotid arterial compliance was lower (P<0.001) in all three postmenopausal groups compared with premenopausal women. Among the postmenopausal groups, arterial compliance was 33-43% higher in the sedentary HRT and endurance-trained women than in their sedentary estrogen-deficient peers. Intervention study. Arterial compliance increased (P<0.05) by approximately 40% to levels that were no longer different than premenopausal women. CONCLUSIONS HRT use and regular aerobic exercise are associated with augmented carotid arterial compliance in healthy postmenopausal women. Moderate, short-term aerobic exercise can restore carotid arterial compliance in previously sedentary postmenopausal women taking HRT.

Overweight and Obese Humans Demonstrate Increased Vascular Endothelial NAD(P)H Oxidase-p47phox Expression and Evidence of Endothelial Oxidative Stress

Background— Obesity may alter vascular endothelial cell protein expression (VECPE) of molecules that influence susceptibility to atherosclerosis. Methods and Results— Quantitative immunofluorescence was performed on vascular endothelial cells collected from 108 men and women free of clinical disease who varied widely in adiposity (body mass index 18.4 to 36.7 kg/m2; total body fat 5.8 to 55.0 kg; waist circumference: 63.0 to 122.9 cm). All 3 expressions of adiposity were positively associated with VECPE of the oxidant enzyme subunit NAD(P)H oxidase-p47phox (part correlation coefficient [rpart] 0.22 to 0.24, all P<0.05) and the antioxidant enzyme catalase (rpart=0.71 to 0.75, all P<0.001). Total body fat was positively associated with VECPE of nitrotyrosine (rpart=0.36, P=0.003), a marker of protein oxidation, and, in men, with Ser1177-phosphorylated endothelial nitric oxide synthase (rpart=0.46, P=0.02), an activated form of endothelial nitric oxide synthase. Overweight/obese subjects (body mass index ≥25 kg/m2) had 35% to 130% higher VECPE of NAD(P)H oxidase-p47phox, nitrotyrosine, catalase, and the cytosolic antioxidant CuZn superoxide dismutase (all P<0.05), as well as a 56% greater VECPE of the potent local vasoconstrictor endothelin-1 (P=0.05) than normal-weight subjects (body mass index <25 kg/m2). Nuclear factor-&kgr;B protein expression was ≈60% to 100% greater in the most obese adults than in the leanest adults (P≤0.01). These relations were independent of sex but were selectively reduced after accounting for the influence of plasma C-reactive protein, fasting glucose-insulin metabolism, or serum triglycerides. Conclusions— Compared with their normal-weight peers, overweight and obese adults demonstrate increased vascular endothelial expression of NAD(P)H oxidase-p47phox and evidence of endothelial oxidative stress, with selective compensatory upregulation of antioxidant enzymes and Ser1177-phosphorylated endothelial nitric oxide synthase. Endothelin-1 and nuclear factor-&kgr;B protein expression also appear to be elevated in obese compared with lean adults. These findings may provide novel insight into the molecular mechanisms linking obesity to increased risk of clinical atherosclerotic diseases in humans.

Vascular Endothelial Estrogen Receptor α Is Modulated by Estrogen Status and Related to Endothelial Function and Endothelial Nitric Oxide Synthase in Healthy Women

CONTEXT AND OBJECTIVE Estrogen receptor alpha (ER alpha), a potent transcription factor expressed in vascular endothelial cells, plays a key role in regulating vascular function and health. We determined whether vascular endothelial cell expression of ER alpha is influenced by estrogen status and is related to vascular endothelial function in healthy women. METHODS ER alpha protein expression was measured (quantitative immunofluorescence) in endothelial cells from peripheral veins of 16 healthy, premenopausal women during the early follicular (EF) and late follicular (LF) phases of the menstrual cycle and 17 estrogen-deficient postmenopausal women. Endothelial-dependent dilation (EDD; brachial artery flow-mediated dilation) and endothelial nitric oxide synthase (eNOS) expression and activation were also measured in a subgroup of women. RESULTS In premenopausal women (n = 10), ER alpha expression was 30% lower (P < 0.001) during the EF (low estrogen) compared with the LF (high estrogen) phase of the menstrual cycle. In postmenopausal women, ER alpha expression was 33% lower (P < 0.001) compared with the LF phase of the menstrual cycle in premenopausal women. ER alpha expression was strongly related (r = 0.67; P < 0.001) to EDD, which was reduced in postmenopausal women. ER alpha abundance was positively related to expression of eNOS (r = 0.54; P = 0.009; n = 21) and ser1177 phosphorylated eNOS (r = 0.59; P = 0.006; n = 20). CONCLUSIONS These results provide the first evidence that expression of ER alpha in vascular endothelial cells is modulated by estrogen status and may be a key determinant of vascular endothelial function in healthy pre- and postmenopausal women. ER alpha expression may influence vascular endothelial function in women by affecting protein levels and activation of eNOS.

Endothelial Function Is Impaired across the Stages of the Menopause Transition in Healthy Women

CONTEXT The stages of the menopause transition are characterized by changes in ovarian hormones and increased cardiovascular disease (CVD) risk factors and vasomotor symptoms that may adversely affect vascular health. OBJECTIVE We tested the hypothesis that endothelial function, a predictor of CVD, would be reduced across the stages of the menopause transition, independent of CVD risk factors and vasomotor symptoms. DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study of 132 healthy women from the general community aged 22-70 yr, categorized as premenopausal (n = 33, 32 ± 6 yr; mean ± SD), early perimenopausal (n = 20, 49 ± 3 yr) or late perimenopausal (n = 22, 50 ± 4 yr), or early (n = 30, 55 ± 3 yr) or late postmenopausal (n = 27, 61 ± 4 yr). MAIN OUTCOME Endothelial-dependent vasodilation was measured by brachial artery flow-mediated dilation (FMD) using ultrasound. RESULTS Brachial artery FMD was significantly different among the groups (P < 0.001). It was highest in premenopausal women (9.9 ± 2.1%) with progressive decrements in perimenopausal (early: 8.2 ± 2.5%; late: 6.5 ± 1.9%) and postmenopausal women (early: 5.5 ± 1.9%; late: 4.7 ± 1.7%). Adjustment for risk factors, vasomotor symptoms, and sex hormones did not alter the association (P < 0.001). In subgroup analyses of women aged 50-59 yr, brachial artery FMD was lower in late peri- and early and late postmenopausal compared with early perimenopausal women (P < 0.001) but was not different between late perimenopausal and either early or late postmenopausal women. CONCLUSIONS Our findings suggest that a decline in endothelial function begins during the early stages of menopause (perimenopause) and worsens with the loss of ovarian function and prolonged estrogen deficiency. These data add to the accumulating evidence that the perimenopausal window is a critical time period for adverse changes in CVD risk.

Effects of Testosterone and Progressive Resistance Exercise in Healthy, Highly Functioning Older Men With Low-Normal Testosterone Levels

CONTEXT Aging in men is associated with reduced testosterone (T) levels and physiological changes leading to frailty, but the benefits of T supplementation are inconclusive. OBJECTIVE We studied the effects of T supplementation with and without progressive resistance training (PRT) on functional performance, strength, and body composition. DESIGN, SETTING, AND PARTICIPANTS We recruited 167 generally healthy community-dwelling older men (66 ± 5 years) with low-normal baseline total T levels (200-350 ng/dL). INTERVENTION Subjects were randomized to placebo or transdermal T gel [2 doses targeting either a lower (400-550 ng/dL) or higher (600-1000 ng/dL) T range] and to either PRT or no exercise for 12 months. MAIN OUTCOME MEASURE The primary outcome was functional performance, whereas secondary outcomes were strength and body composition. RESULTS A total of 143 men completed the study. At 12 months, total T was 528 ± 287 ng/dL in subjects receiving any T and 287 ± 65 ng/dL in the placebo group. In the PRT group, function and strength were not different between T- and placebo-treated subjects, despite greater improvements in fat mass (P = .04) and fat-free mass (P = .01) with T. In the non-PRT group, T did not improve function but improved fat mass (P = .005), fat-free mass (P = .03), and upper body strength (P = .03) compared with placebo. There were fewer cardiovascular events in the T-treated groups compared with placebo. CONCLUSIONS T supplementation was well tolerated and improved body composition but had no effect on functional performance. T supplementation improved upper body strength only in nonexercisers compared with placebo.

Modulatory influences on ageing of the vasculature in healthy humans.

Increased arterial stiffness and impaired vascular endothelial function are the two most clinically important events that occur with vascular ageing in humans. Together they contribute to age-associated increases in systolic hypertension, left ventricular remodeling and diastolic dysfunction, coronary artery and other atherosclerotic vascular diseases, congestive heart failure, and the attendant cardiac events such as myocardial infarction. However, there is marked individual variability in arterial stiffness and endothelial function with advancing age, which suggests modulation by one or, more likely, several biological and/or lifestyle factors. Consistent with this idea, habitual aerobic exercise appears to attenuate or completely prevent these adverse changes. Other factors including sex hormone status, circulating total and low-density lipoprotein-cholesterol levels, total body and abdominal fatness, and dietary sodium intake also appear to influence arterial stiffening and endothelial dysfunction with ageing. It is now clear that a number of physiological factors and lifestyle behaviors collectively determine how much and, perhaps in some cases, if functionally or clinically significant vascular ageing occurs in adult humans. Of these, the existing evidence indicates that habitual aerobic exercise may be the single most important modulatory influence.

Ascorbic Acid Selectively Improves Large Elastic Artery Compliance in Postmenopausal Women

The compliance of large elastic arteries in the cardiothoracic region decreases with advancing age/menopause and plays an important role in the increased prevalence of cardiovascular diseases in postmenopausal women. We determined whether oxidative stress contributes to the reduced large elastic artery compliance of postmenopausal women. Carotid artery compliance was measured during acute intravenous infusions of saline (baseline control) and supraphysiological doses of the potent antioxidant ascorbic acid in premenopausal (n=10; 23±1; mean±SE) and estrogen-deficient postmenopausal (n=21; 55±1 years) healthy sedentary women. Carotid artery compliance was 56% lower in postmenopausal compared with premenopausal women during baseline control (P<0.0001). Ascorbic acid infusion increased carotid artery compliance by 26% in postmenopausal women (1.11±0.07 to 1.38±0.08 mm2/mm Hg×10−1; P<0.001) but had no effect in premenopausal women (2.50±0.25 versus 2.43±0.20 mm2/mm Hg×10−1). Carotid artery diameter, blood pressure, and heart rate were unaffected by ascorbic acid. In the pooled population, the change in arterial compliance with ascorbic acid correlated with baseline waist-to-hip ratio (r=0.56; P=0.001), plasma norepinephrine (r=0.58; P=0.001), and LDL cholesterol (r=0.54; P=0.001). These results suggest that oxidative stress may be an important mechanism contributing to the reduced large elastic artery compliance of sedentary, estrogen-deficient postmenopausal women. Increased abdominal fat storage, sympathetic nervous system activity, and LDL cholesterol may be mechanistically involved in oxidative stress–associated suppression of arterial compliance in postmenopausal women.

Essential role of estrogen for improvements in vascular endothelial function with endurance exercise in postmenopausal women.

OBJECTIVE In contrast to age-matched men, endurance exercise training is not consistently associated with enhanced endothelial function in estrogen-deficient postmenopausal women. We determined whether endurance exercise training improves endothelial function in postmenopausal women treated with estrogen. In a substudy, we determined if oxidative stress is mechanistically linked to endothelial function adaptations to endurance exercise training. PARTICIPANTS AND DESIGN Brachial artery flow-mediated dilation (FMD) was measured in 36 sedentary, estrogen-deficient postmenopausal women (45-65 y) at study entry (baseline), after 12 weeks of either placebo, oral (1 mg/d) estradiol, or transdermal estradiol (0.05 mg/d) (randomized), and after an additional 12 weeks of continued estradiol or placebo treatment with concurrent endurance exercise training. In subgroups of women, FMD also was measured during the infusion of ascorbic acid at baseline and following estradiol/placebo plus endurance exercise training, and in seven habitually endurance-trained estrogen-deficient controls. RESULTS FMD increased in the estrogen-treated groups (both P < .01) after 12 weeks and remained unchanged in placebo. FMD further increased following 12 weeks of endurance exercise training in estrogen-treated (both P < .025), but not placebo-treated women (P = .55). In the substudy, baseline FMD was similar between sedentary and endurance-trained controls. Ascorbic acid increased FMD at baseline in sedentary women and endurance-trained controls, and following endurance exercise training in placebo-treated, but not in estrogen-treated women. CONCLUSIONS Estrogen status appears to play an important modulatory role in improvements in endothelial function with endurance exercise training in postmenopausal women. The restored endurance exercise training adaptation in estrogen-treated postmenopausal women may be related to mitigation of oxidative stress.

Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women

The mechanisms mediating arterial stiffening with aging and menopause are not completely understood. We determined whether administration of tetrahydrobiopterin (BH(4)), a critical cofactor for endothelial nitric oxide synthase to produce nitric oxide, would increase vascular endothelial-dependent vasodilatory tone and decrease arterial stiffness in estrogen-deficient postmenopausal women. Additionally, we examined whether the beneficial effects of estrogen on vascular function were possibly related to BH(4). Arterial stiffness (carotid artery compliance) and endothelial-dependent vasodilation [brachial artery flow-mediated dilation (FMD)] were measured in postmenopausal (n = 24; 57 ± 1 yr, mean ± SE) and eumenorrheic premenopausal (n = 9; 33 ± 2 yr) women before and 3 h after the oral administration of BH(4). Subsequently, in postmenopausal women, vascular testing (before and after BH(4)) was repeated following randomization to either 2 days of transdermal estradiol or placebo. Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than in premenopausal women (P < 0.0001). BH(4) administration increased carotid artery compliance (0.61 ± 0.05 to 0.73 ± 0.04 mm(2)·mmHg(-1)·10(-1) vs. baseline, P < 0.0001) and brachial artery FMD (P < 0.001) in postmenopausal women but had no effect in premenopausal women (P = 0.62). Carotid artery compliance (0.59 ± 0.05 to 0.78 ± 0.06 mm(2)·mmHg(-1)·10(-1), P < 0.001) and FMD increased in postmenopausal women in response to estradiol (P = 0.02) but were not further improved with the coadministration of BH(4), possibly because estrogen increased BH(4) bioavailability. Carotid artery compliance and FMD increased with BH(4) in the placebo group (P = 0.02). Although speculative, these results suggest that reduced vascular BH(4) may be an important contributor to arterial stiffening in estrogen-deficient postmenopausal women, related in part to reduced endothelial-dependent vasodilatory tone.