Endothelial Function In Postmenopausal Women Research Articles

Abstract P217: The Role Of Angiotensin-(1-7) In Regulating Vascular Endothelial Function In Postmenopausal Women

Postmenopausal women (PMW) have reduced endothelial function, however, the mechanisms contributing to this decline remain unclear. Angiotensin-(1-7) [Ang-(1-7)] is a vasoactive peptide of the vasodilatory arm of the Renin-Angiotensin system and increasing bioavailable Ang-(1-7) enhances endothelial function in young women (YW) with pre-clinical cardiovascular disease. Circulating Ang-(1-7) decreases with aging and may be impacted by menopause. However, whether increasing bioavailable Ang-(1-7) improves endothelial function in PMW is unknown. The purpose of this study was to test the hypothesis that increasing bioavailable Ang-(1-7) improves endothelial function in PMW. We assessed skin blood flow responses to local heating in 8 healthy YW (27±9 yrs) and 5 healthy PMW (56±4 yrs). Cutaneous vasodilation was measured using laser-Doppler flowmetry directly over microdialysis perfusions of lactated Ringer’s (control) in YW and PMW, and in PMW only, 100 μM Ang-(1-7). Following 45 minutes of perfusion of lactated Ringer’s and Ang-(1-7), skin was heated to 42°C (0.1°C·sec -1 ) until laser-Doppler flux reached a stable plateau, indicative of endothelium-dependent dilation. Following the plateau, 28mM sodium nitroprusside was perfused while skin was heated to 43°C to achieve maximal vasodilation. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/MAP, and normalized to maximal dilation (%CVC max ). Women were normotensive (MAP: YW 86±7 mmHg; PMW 85±9 mmHg) and not obese (BMI: YW 23±3 kg/m 2 ; PMW 23±4 kg/m 2 ). YW had greater dilation during local heating (control: YW 94.54±5.4 vs. PMW 82.59±10.72 %CVC max ; P=0.021). Contrary to our hypothesis, Ang-(1-7) did not enhance heating-induced vasodilation in PMW (80.10±9.43 %CVC max ; P=0.69). These preliminary results suggest that increasing bioavailable Ang-(1-7) may not improve endothelial function in PMW. Additional studies are needed to understand if these findings are due to estrogen deficiency in PMW.

OR26-05-23 The Influence of 7-Day Dietary Nitrate Supplementation on Resting Endothelial Function in Post-Menopausal Women

OR26-05-23 The Influence of 7-Day Dietary Nitrate Supplementation on Resting Endothelial Function in Post-Menopausal Women

Aerobic exercise training reduces ET-1-mediated vasoconstriction and improves endothelium-dependent vasodilation in postmenopausal women.

Endothelin-1 (ET-1) contributes to vascular dysfunction in postmenopausal women (PMW). Although aerobic exercise is beneficial in reducing ET-1-mediated vasoconstrictor tone in men, it is unknown whether this favorable vascular effect occurs in women. We tested the hypothesis that aerobic exercise training reduces ET-1-mediated vasoconstriction in PMW. We further hypothesized that reductions in ET-1 vasoconstrictor tone underly exercise-induced improvements in endothelium-dependent vasodilatation in PMW. Forearm blood flow (FBF) responses to intra-arterial infusion of selective ETA receptor blockade (BQ-123, 100 nmol/min for 60 min) and acetylcholine (4.0, 8.0, and 16.0 μg/100 mL tissue/min) in the absence and presence of ETA receptor blockade were determined before and after a 12-wk aerobic exercise training intervention in 18 healthy, sedentary PMW (58 ± 4 yr). Women exercised an average of 4.9 ± 0.7 day/wk for 51 ± 7 min/day at 71 ± 3% of maximal heart rate. Before exercise, BQ-123 significantly increased FBF (∼25%) in sedentary PMW; however, this effect was abolished following the exercise intervention. FBF responses to acetylcholine were also significantly higher after exercise training (from 4.2 ± 1.2 to 14.0 ± 3.8 mL/100 mL tissue/min) versus before (from 4.1 ± 1.0 to 11.4 ± 3.3 mL/100 mL tissue/min; ∼25% increase; P < 0.05). Before exercise training, coinfusion of BQ-123 with acetylcholine enhanced (∼25%; P < 0.05) the vasodilator response (from 4.4 ± 1.1 to 13.9 ± 4.2 mL/100 mL tissue/min) compared with acetylcholine alone; after exercise training, the presence of BQ-123 did not significantly affect the vasodilator response to acetylcholine. Aerobic exercise training reduces ET-1-mediated vasoconstriction in PMW. Furthermore, decreased ET-1-mediated vasoconstriction is an important mechanism underlying aerobic exercise-induced improvement in endothelium-dependent vasodilation in PMW.NEW & NOTEWORTHY Endothelin-1 (ET-1) contributes to declines in endothelial function in postmenopausal women. To our knowledge, we show for the first time that aerobic exercise reduces ET-1-mediated vasoconstriction in previously sedentary postmenopausal women. Moreover, aerobic exercise improved endothelial-dependent dilation due in part to the reductions in ET-1-mediated vasoconstriction.

Regular Tennis Exercise May Improve the Vascular Endothelial Function in Postmenopausal Women: The Influence of Hemodynamics

Physical inactivity plays a role in the incidence of cardiovascular disease (CVD). Although the current guidelines for physical activity, such as the prescription of exercise, seek to combat CVD, attaining the recommended targets remains challenging. Tennis exercise has been proven to have a unique advantage in reducing the mortality of CVD, but little is known about the influence of playing tennis on impaired vascular endothelial function (VEF), which initiates CVD. Thus, this study aimed to investigate whether regular tennis participation could protect the VEF better than merely meeting the physical activity recommended by the current guidelines. A cross-sectional design was performed based on a sample of 38 healthy postmenopausal women who were matched for physical activity, of which 17 subjects had long-term tennis experience and 21 age-matched subjects regularly exercised but did not play tennis. The cardiovascular function and the body composition of all subjects were measured. We used cluster analysis to assess the overall health status. The modeling results showed that the tennis players performed better in terms of VEF than the nonplayers (10.55 ± 0.58 vs. 8.69 ± 0.52, p < 0.01, R2ad = 0.367), while the wall shear stress positively correlated with VEF (r = 0.505, p < 0.05), after controlling for age and physical activity levels. Regular tennis exercise may be a protective factor for VEF, and further study should be performed to research the role of hemodynamics in tennis exercise.

Inspiratory muscle strength training for lowering blood pressure and improving endothelial function in postmenopausal women: comparison with "standard of care" aerobic exercise.

Background: High blood pressure (BP), particularly systolic BP (SBP), is the major modifiable risk factor for cardiovascular diseases and related disorders of aging. SBP increases markedly with aging in women such that the prevalence of above-normal SBP (i.e., ≥120 mmHg) in postmenopausal women exceeds rates in age-matched men. This increase in SBP is associated with vascular endothelial dysfunction, mediated by excessive reactive oxygen species-induced oxidative stress and consequent reductions in nitric oxide bioavailability. Moderate-intensity aerobic exercise is a recommended lifestyle strategy for reducing SBP. However, adherence to aerobic exercise guidelines among postmenopausal women is low (<30%) and aerobic exercise does not consistently enhance endothelial function in estrogen-deficient postmenopausal women. High-resistance inspiratory muscle strength training (IMST) is a time-efficient, adherable lifestyle intervention that involves inhaling against resistance through a handheld device (30 breaths/day). Here, we present the protocol for a randomized controlled trial investigating the efficacy of 3 months of high-resistance IMST compared to guideline-based, “standard-of-care” aerobic exercise training for decreasing SBP and improving endothelial function in estrogen-deficient postmenopausal women with above-normal SBP (120–159 mmHg) at baseline (ClinicalTrials.gov Identifier: NCT05000515). Methods: A randomized, single-blind, parallel-group design clinical trial will be conducted in 72 (36/group) estrogen-deficient postmenopausal women with above-normal SBP. Participants will complete baseline testing and then be randomized to either 3 months of high-resistance IMST (30 breaths/day, 6 days/week, 75% maximal inspiratory pressure) or moderate-intensity aerobic exercise training (brisk walking 25 min/day, 6 days/week, 40–60% heart rate reserve). Outcome measures will be assessed after 3 months of either intervention. Following end-intervention testing, participants will abstain from their assigned intervention for 6 weeks, after which BP and endothelial function will be assessed to evaluate the potential persistent effects of the intervention on the primary and secondary outcomes. Discussion: This study is designed to compare the effectiveness of time-efficient, high-resistance IMST to guideline-based aerobic exercise training for lowering SBP and improving endothelial function, and interrogating potential mechanisms of action, in estrogen-deficient postmenopausal women. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT05000515.

Endothelial Function in Postmenopausal Women: The Possible Role of Heat Shock Protein 60 and Serum Androgens.

Background: Heat shock protein 60 (HSP60), a potentially homeostatic antigen, is involved in physiological and non-physiological conditions. Experimental data support the role of HSP60 in placental and mitochondrial steroidogenesis. Furthermore, HSP60 is translocated into the endothelial-cell plasma membrane and the extracellular space under stress conditions, promoting the atherosclerotic process. Therefore, we investigated the association between HSP60 and endothelial function in postmenopausal women, considering the possible atherogenic effect of androgenic hormones. Methods: This study included 123 healthy postmenopausal women. Exclusion criteria were treated hypertension or dyslipidaemia, menopause hormone therapy during the last 6months, and previously diagnosed peripheral vascular disease or cardiovascular disease. Fasting venous blood samples were obtained for biochemical and hormonal assessment and evaluation of HSP60. Sonographic assessment of flow-mediated dilation (FMD) occurred immediately after that in one session. Results: Univariate analysis showed that women with FMD values below median 5.12% had lower logHSP60 values (low vs. high FMD, HSP60 values: 2.01 ± 1.16ng/ml vs. 3.22 ± 1.17ng/ml, p-value = 0.031). Multivariable analysis showed that logHSP60 was associated with FMD (b-coefficient = 0.171, p-value = 0.046), adjusting for traditional cardiovascular risk factors (TRFs) and insulin levels. Further adjustment for testosterone and DHEAS rendered the result non-significant. In the multivariable analysis, FMD was associated with insulin (b-coefficient = -0.166, p-value = 0.034), testosterone (b-coefficient = -0.165, p-value = 0.034), DHEAS (b-coefficient = -0.187, p-value = 0.017), adjusting for TRFs. Discussion: The results of this study indicate that the association between androgens and endothelial function is possibly mediated by HSP60 molecules, in women with low insulin resistance and androgenicity. Further prospective studies are needed to explore the significance of our findings.

Blueberries Improve Endothelial Function in Postmenopausal Women With Above-Normal Blood Pressure via Reductions in Oxidative Stress

ObjectivesResearch suggests blueberries and their (poly)phenols may improve endothelial dysfunction, a major risk factor for cardiovascular disease (CVD). The objective of this study was to investigate the impact of consuming 22 g/day for 12 weeks of freeze-dried highbush blueberry powder on endothelial function and other measures of cardiovascular health, oxidative stress, and circulating (poly)phenol metabolites in postmenopausal women with above-normal blood pressure.MethodsWe performed a randomized, double-blind, placebo-controlled, parallel-arm trial in estrogen-deficient postmenopausal women aged 45–65 years with elevated blood pressure or stage 1-HTN. Endothelial function was assessed as brachial artery flow-mediated dilation (FMD) and normalized to individual shear rate area under the curve (FMD/SRAUC) to control for inter-individual variability in reactive hyperemia-induced shear stress. To assess whether improvements in FMD were mediated by reduced oxidative stress, FMD was assessed before and after intravenous infusion of a supra-physiologic dose of ascorbic acid. Blood pressure, arterial stiffness, and plasma (poly)phenol metabolites were also assessed.ResultsA total of 43 women completed the trial (n = 32 for endothelial function). Compliance in the Blueberry and Placebo groups were 93% and 91%, respectively. Mean total plasma (poly)phenol metabolite concentrations were increased at 4 (250,053 nmol/L, P < 0.05) and 8 (303,053 nmol/L, P < 0.05) weeks in the Blueberry group compared to baseline (125,798 nmol/L) with a strong trend at 12 weeks (227,971 nmol/L, P < 0.05), and no changes in Placebo. Blood pressure and arterial stiffness were unchanged with both treatments. At 12 weeks, FMD/SRAUC was increased by 96% from baseline (P < 0.05) in the Blueberry group but unchanged in Placebo, and changes in FMD/SRAUC from baseline to 12 weeks were higher (P < 0.05) than Placebo. The response in FMD/SRAUC to ascorbic acid infusion was lower (P < 0.05) at 12 weeks compared to baseline in the Blueberry group but not Placebo.ConclusionsThese findings suggest blueberries improve endothelial function, and is mediated, in part, by reduced oxidative stress in postmenopausal women with above-normal blood pressure, a high-risk population for developing CVD.Funding SourcesUS Highbush Blueberry Council and USDA National Institute of Food and Agriculture.

Heat shock protein 60 and Endothelial function in postmenopausal women

Heat shock protein 60 and Endothelial function in postmenopausal women

Impact of metabolic syndrome and systemic inflammation on endothelial function in postmenopausal women.

Data on the impact of metabolic syndrome (MetS) and systemic inflammation on endothelial function remains scarce. In this study, we aimed to investigate the combined effects of MetS and systemic inflammation on endothelial function in postmenopausal women. We identified 423 postmenopausal women from February 2019 through July 2020. MetS was diagnosed according to the International Diabetes Federation (IDF) criteria, and high sensitivity C-reaction protein (hs-CRP) was measured to assess the degree of underlying inflammation. The measurement of endothelial function was using digital arterial tonometry by assessing reactive hyperemia-induced vasodilation in one arm and adjusting for changes in the contralateral arm (reactive hyperemia index, RHI). There were 156 patients with MetS and 267 without MetS. Compared to the group without MetS, patients with MetS had significantly lower natural logarithmic RHI (0.66±0.29 versus 0.91±0.31; p<0.001), but higher levels of hs-CRP (0.98 [0.31, 3.54] versus 0.53 [0.20, 2.14]; p<0.001). In sequential multivariable analysis, the presence of hs-CRP (ΔR2=0.047, p=0.004) had a significant and independent influence on natural logarithmic RHI. Furthermore, the interaction of hs-CRP*MetS was synergistically associated with endothelial dysfunction even in the fully adjusted model (β=-0.107, 95% CI [-0.161~-0.053], p=0.009). MetS and systemic inflammation are synergistically associated with endothelial dysfunction in postmenopausal women. Postmenopausal women with both these conditions appear to be at a significantly higher risk for adverse cardiovascular events.

The effect of tibolone treatment on fasting blood sugar, insulin, insulin resistance and endothelial function in postmenopausal women: A meta-analysis of randomized controlled trials.

The menopause is associated in females with the presence of dysglycemia, insulin resistance and with the development of endothelial dysfunction. Tibolone (TIB) is a synthetic steroid compound with selective oestrogenic and, to a lesser extent, progestogenic and androgenic properties prescribed to postmenopausal women to alleviate the symptoms of the climaterium and to prevent the development of osteoporosis. However, the impact of TIB on fasting blood sugar (FBS), insulin, Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) index and flow-mediated dilation (FMD) in women has not been evaluated so far. Thus, to investigate this research question, we conducted the present systematic review and meta-analysis. Two independent reviewers searched the Scopus, Web of Science, PubMed/Medline and Embase databases up to 20 December 2020. The weighted mean differences (WMDs) and the 95% confidence intervals (CI) were calculated using the DerSimonian and Laird random effects models between the TIB and control groups and included in the forest plot. The overall findings were generated from 12 eligible randomized controlled trials. As compared to controls, TIB administration resulted in a significant reduction of FBS (WMD: -3.06mg/dL, 95% CI: -5.30 to -0.82, P=0.007), and of the HOMA-IR index (WMD: -0.61, 95% CI: -1.11 to -0.11, P=0.01). However, treatment with TIB did not lead to significant changes of the FMD (WMD: 0.78%, 95% CI: -0.20 to 1.77, P=0.12) or of insulin levels (WMD: -0.10 mIU/L, 95% CI: -2.04 to 1.83, P=0.91). TIB administration can decrease FBS and the HOMA-IR index in postmenopausal women. However, the use of TIB does not influence insulin levels or FMD.

Cerebrovascular reactivity is related to peripheral endothelial function among healthy postmenopausal women but not midlife and older men

Background Age is the primary risk factor for cardiovascular diseases (CVD), cognitive decline, Alzheimer's disease and related dementias. Young women are at a lower risk for the above-mentioned diseases compared to age-matched men; however, their risk becomes greater than men after menopause. Age-related declines in peripheral and cerebral vascular function are thought to play a role in the increased risk for CVD and related chronic conditions. It is often assumed that changes in peripheral vascular function are directly indicative of changes in cerebrovascular function. However, in young, healthy adults, there does not appear to be an association between peripheral and cerebral vascular function. There is still limited evidence for whether peripheral vascular function is indicative of cerebrovascular function in postmenopausal (PM) women and midlife and older (ML/O) men. Purpose To determine the relation between cerebrovascular reactivity (CVR; an index of cerebrovascular function) and vascular endothelial function (brachial artery flow-mediated dilation [FMDBA]) in PM women and ML/O men and to determine if cerebrovascular function is associated with cognitive function in these groups. Methods CVR, FMDBA, and cognitive function were assessed in 17 PM women (67±6 years) and 26 men (66±7 years). Middle cerebral artery velocity (MCAv; cm/s) using a 2-MHz transcranial Doppler probe and end-tidal CO2 (etCO2; mmHg) were measured during 5 minutes of normocapnia and 5 minutes of hypercapnia (5% CO2). CVR was calculated as ΔMCAv/ΔetCO2. FMDBA was determined with the forearm cuff method and data expressed as Δ% from baseline diameter. The NIH Toolbox Cognition Battery of tests was used to assess global cognitive function, as well as specific cognitive domains. Results CVR was correlated with FMDBA (r=0.33, p=0.02) in PM women but was not correlated with FMDBA in ML/O men (r<0.01, p=0.85). There was a significant difference in this relation between sexes (p=0.04). Stepwise linear regression identified CVR and body mass index (BMI), but not age, blood pressures, LDL and HDL cholesterol, triglycerides or glucose, as significantly related to FMD­BA in PM women; correcting for BMI strengthened the relation between CVR and FMDBA in PM women (r=0.62, p<0.01). In contrast, only plasma LDL cholesterol and triglycerides were significantly related to FMD­BA in ML/O men. There were no relations between CVR and cognitive function in PM women (all p>0.05). In men there was a significant positive relation between CVR and the picture vocabulary test measure of language (r=0.56, p<0.01), but no other measures of cognitive function (all p>0.05). Conclusions These findings suggest cerebrovascular function is associated with peripheral vascular endothelial function in PM women, but not ML/O men, while cerebrovascular function has no to minimal relation to cognitive function in these groups. Controlling for BMI increased the strength of the relation between CVR and FMD­BA in PM women, indicating that body composition may be an important factor influencing cerebrovascular function in these women.

Effect of soy protein containing isoflavones on endothelial and vascular function in postmenopausal women: a systematic review and meta-analysis of randomized controlled trials.

The beneficial role of soy protein in cardiovascular health has been well documented in observational studies. However, evidence from clinical trials on effects of soy protein on endothelial function in postmenopausal women has been conflicting. We aimed to systematically review and conduct a meta-analysis of randomized controlled trials (RCTs) investigating the impact of soy protein supplement containing isoflavones on endothelial function in postmenopausal women. We searched PubMed-Medline, SCOPUS, Embase, and Google Scholar until March 2020 to find RCTs evaluating the impact of soy protein supplementation on endothelial function parameters. Random effects model (using DerSimonian-Laird method) was applied to synthesize quantitative data. We performed the leave-one-out method for sensitivity analysis. To quantitatively assess heterogeneity, the I index was applied. From a total of 267 studies identified from the initial search 15 and 5 studies were considered appropriate for inclusion into the systematic review and meta-analysis, respectively. In the meta-analysis, an insignificant enhancement in flow-mediated dilation (FMD) after soy protein supplementation (0.882%; 95% CI: -1.059 to 2.822; P = 0.373) was found. However, subgroup analysis showed that supplementation of isolated soy protein had significant effect on FMD (3.39%; 95% CI: 0.733-6.01; P = 0.01). Our findings suggest that soy protein supplementation does not lead to meaningful improvement in FMD in postmenopausal women. However, this finding is based on a limited number of studies. Additional high-quality large-scale RCTs are warranted.

The Diversity Effect Of Exercise On Endothelialfunction In Postmenopausal Women With ACE D/I Polymorphism

PURPOSE: Increased incidences of cardiovascular disorder and metabolic syndrome particularly in postmenopausal women have raised curiosity for the underlying factors. One potential mechanism by which endothelial dysfunction may promote early arterial stiffness is by causing estrogen deficiency. It is reported that physical exercise counteracts the occurrence of above disorders, while a few others show no change. The training response differs among individuals partly due to genetic composition. Angiotensin-converting enzyme (ACE) insertion/deletion (D/I) polymorphism related to physical performance in athletes has been well-reported. The present study was to observe the effects of 12 weeks exercise (aerobic exercise and resistance training) on endothelial function in postmenopausal women with different D/I polymorphism of ACE gene. METHODS: 122 postmenopausal women aged 45-75 years were randomly divided into aerobic exercise group (DI/II=65, DD=6) and resistance training group (DI/II=42, DD=9). Body composition, TC, HDL, LDL, endothelial function, endothelium-derived relaxing factor and contracting factor were analyzed. RESULTS: TC, blood lipid abnormality rate, blood glucose and visceral fat in DI/II type were decreased more significantly after aerobic exercise compared with DD type. Aerobic exercise showed markedly positive effects in LDL, hyperglycemia, overweight/obesity, high body fat rate, abnormal waist-hip ratio and visceral fat in DI/II, while resistance training in LDL, blood glucose (5.34±0.73 vs 4.46±0.34mmol/l, P<0.01), waist-hip ratio and visceral fat (96.60±13.84 vs 61.33±8.65cm2, P<0.05) in DD type. Aerobic exercise showed more obviously increased FMD (9.65±1.85 vs 11.00±1.99%, P<0.05), NO (68.31±4.67 vs 76.38±4.01umol/l, P<0.05), NO/ET-1 (0.91±0.11 vs 1.04±0.11, P<0.05) and decreased SBP (123.84±15.98 vs 109.89±13.56mmHg, P<0.05), DBP in DI/II than in DD type. Resistance training increased FMD (7.12±0.70 vs 9.56±0.78%, P<0.05), NO/ET-1 and decreased SBP, DBP, baPWV, ET-1, AngII more significantly in DD type than in DI/II type. CONCLUSIONS: Exercise positively influences endothelial functions, independent of ACE D/I polymorphism; and DI/II carriers show a better response to aerobic exercise, while DD carriers to resistance exercise.

Altered endothelial ETB receptor expression in postmenopausal women.

The endothelin system plays an important role in mediating vascular function. The endothelin-B receptor (ETBR) on endothelial cells mediates vasodilation via nitric oxide production. The vasodilatory effect of the ETBR is lost following menopause and may contribute to impaired vascular endothelial function in postmenopausal women (PMW). However, it is unclear if these functional changes are due to changes in ETBR expression on the endothelium. Therefore, the purpose of this study was to test the hypothesis that endothelial cell ETBR expression is lower in PMW compared with young women (YW). Primary endothelial cells were harvested from the antecubital vein of healthy PMW (n = 15, 60 ± 6 yr) and YW (n = 15, 22 ± 2 yr). Cells were identified as endothelial cells by staining for vascular endothelial cadherin, and nuclear integrity was assessed using 4',6-diamidino-2-phenylindole (DAPI). Within those cells, ETBR was quantified using immunocytochemistry; fluorescence intensity was measured in 30 cells and averaged for each participant. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD). Endothelial cell ETBR expression was lower in PMW [0.46 ± 0.11 arbitrary units (AU)] compared with YW (0.58 ± 0.14 AU; P = 0.02). Furthermore, significant correlations between ETBR expression and FMD (r = 0.47, P < 0.01), total cholesterol (r = -0.38, P = 0.04), and LDL cholesterol (r = -0.39, P = 0.03) were observed. These data demonstrate that endothelial cell ETBR expression is attenuated in PMW. These novel findings provide additional insight into the mechanisms underlying vascular endothelial dysfunction in PMW.NEW & NOTEWORTHY Our study provides novel data demonstrating attenuated endothelial ETBR expression in postmenopausal women. Furthermore, our data extend current knowledge by demonstrating a positive relation between ETBR expression and brachial artery flow-mediated dilation. These findings provide additional mechanistic insight into vascular endothelial dysfunction in postmenopausal women.

Effects of Grape Seed Extract Supplementation on Hemodynamic Response and Vascular Endothelial Function in Postmenopausal Women

The article's abstract is no available.

Sex differences in ET‐1 levels in primary human endothelial cells

Endothelin‐1 (ET‐1) is produced and secreted primarily by endothelial cells and acts as a potent vasoconstrictor. Our laboratory has previously shown that ET‐1 contributes to impaired vascular endothelial function in postmenopausal women (PMW). However, compared to PMW, ET‐1 mediated vasoconstriction is greater in men of a similar age. Although sex differences in ET‐1 receptor expression and/or responses may partially explain these differences, it is unknown whether ET‐1 levels in endothelial cells differ between PMW and men of similar age. The purpose of this study was to test the hypothesis that PMW have lower endothelial cell ET‐1 levels compared to men of similar age. Endothelial cells were harvested from the antecubital vein of healthy PMW (n=9, 59±3 yrs) and age‐matched men (n=7, 58±6 yrs) by threading a guide wire through an 18g IV catheter. The guide wire was rinsed in dissociation buffer to remove endothelial cells, which were then fixed in 4% paraformaldehyde, washed in phosphate buffered saline, pipetted onto coverglass, dried at 60°C, and stored at −80°C until staining. Immunocytochemistry was used to stain for ET‐1 (Endothelin‐1 Monoclonal Antibody (TR.ET.48.5), Thermo Fisher Scientific, Cat# MA3‐005), vascular endothelial cadherin (VE‐Cadherin polyclonal antibody, Thermo Fisher Scientific, Cat# 36‐1900) to identify endothelial cells, and 4′,6‐diamidino‐2‐phenylindole (DAPI, nuclear stain). Fluorescence intensity was measured in 30 cells on a Zeiss Axio imager using consistent laser intensity and exposure times. ET‐1 intensity was normalized to human umbilical vein endothelial cells, consistent with published literature. Results are reported as mean ± standard deviation. PMW and men were well match based on BMI (PMW; 25±5 kg/m2 vs. Men; 25±3), mean arterial blood pressure (PMW; 88±8 vs. Men; 93±9 mmHg), total cholesterol (PMW; 193±45 vs. Men; 192±40 mg/dL), LDL cholesterol (PMW; 103±39 vs. Men; 111±34 mg/dL), and fasting plasma glucose (PMW; 88±4 vs. Men; 92±6 mg/dL) all P&gt;0.05. ET‐1 intensity levels were significantly lower in PMW (0.57±0.12 a.u) compared to Men (0.98±0.27 a.u, P =0.001). These preliminary findings suggest differences in endothelial ET‐1 levels between PMW and age‐matched men. Moreover, these data provide further evidence of the sexual dimorphisms in the ET‐1 system, and add insight into mechanisms underlying sex differences in vascular function.Support or Funding InformationNIH R01 HL 146558, HL‐113514, P20 GM 113125, AHA 16SDG30700015, and University of Delaware Research Foundation.

ETB Receptor Function is Modulated by Estradiol in Young Women

It is well known that vascular endothelial function declines in women after menopause. Our laboratory has recently shown that impaired endothelial function in postmenopausal women is due in part to a loss of endothelin‐B (ETB) receptor mediated dilation. However, it is unclear whether these changes in ETB function are due to aging or menopause‐related declines in ovarian hormones. Therefore, the purpose of this study was to test the hypothesis that short‐term estradiol (E2) administration would enhance the contribution of ETB receptor mediated dilation during local heating in young women. Twelve young women (24 ± 4 years, 24 ± 3 kg/m2, mean arterial blood pressure: 84 ± 6 mm Hg) participated in this study. Endogenous sex hormone production was suppressed with daily administration of a gonadotropin‐releasing hormone antagonist (GnRHant; Ganirelix) for 10 days. E2 (0.1 mg/day, Vivelle dot patch) was added back on days 4–10. We measured cutaneous vasodilation to local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant+E2) via laser Doppler flowmetry coupled with intradermal microdialysis for the perfusion of lactated Ringer’s (control) and ETB receptor antagonist (BQ‐788, 300 nM). Cutaneous vascular conductance (CVC) was calculated as cutaneous red blood cell flux/mean arterial blood pressure, and expressed as a percent of maximal vasodilation (CVC %max) achieved with local heating to 43°C and perfusion of sodium nitroprusside (28 mM). E2 administration improved cutaneous vasodilation by 8 ± 10% (control site; P = 0.02) compared to GnRHant. ETB receptor blockade increased cutaneous vasodilation to local heating during hormone suppression with GnRHant (control: 84 ± 7 vs. BQ‐788: 89 ± 5 CVC %max, P = 0.02). However, ETB receptor blockade tended to reduce cutaneous vasodilation to local heating during short duration E2 administration (control: 90 ± 7 vs. BQ‐788: 85 ± 8 CVC %max, P = 0.08). These data indicate that suppression of endogenous ovarian hormone production alters ETB receptor responses in young women, mimicking the response profile in postmenopausal women observed in our previous data. Furthermore, these data suggest that E2 modulates ETB receptor function. Additional data are needed to determine ETB receptor function and sensitivity to E2 in postmenopausal women.Support or Funding InformationResearch supported by AHA Award 16SDG30700015 (MMW), NIH Grant U54‐GM104941 (PI: Binder‐Macleod), and P20 GM113125 (DGE).

Effects of exergaming in postmenopausal women with high cardiovascular risk: A randomized controlled trial

ObjectiveRecently, exergames have been used an exercise modality as aerobic fitness activities. However, evidence of its effectiveness on cardiovascular (CV)‐related risk factors remain unclear.HypothesisWe evaluate the effects of exergaming on CV‐related risk factors compared with traditional aerobic exercise in high CV risk patients.MethodsSixty‐five postmenopausal women with high CV risk were randomized among exergame (n = 22), treadmill (n = 22), and control (n = 21) groups. The exergame group was engaged in the running‐based exergame using Exer Heart and the treadmill group walked or jogged on a treadmill. Cardiorespiratory fitness, flow‐mediated dilation, endothelial progenitor cells (EPCs), epicardial fat thickness, metabolic parameters, and anthropometric parameters were measured in patients before and 12 weeks after the training.ResultsExergaming significantly improved VO2 peak (P < .001; different from control, P < .05), flow‐mediated dilation (P < .001; different from control, P < .05), EPCs (CD34/CD117+, P < .01). Treadmill exercise was effective at improving VO2 peak (P < .01; different from control, P < .05), flow‐mediated dilation (P < .05), EPCs (CD34/CD117+, P < .01; different from control P < .05). Epicardial fat thickness decreased after both exercise programs (exergame, P < .01; treadmill, P < .01; no different from control).ConclusionExergaming showed similar effects to traditional aerobic exercise in improving cardiorespiratory fitness and endothelial function in postmenopausal women with high CV risk. These findings suggest that the exergames may serve as an alternative to conventional aerobic exercises for prevention and treatment in high CV risk patients.

Endogenous Sex Hormones and Endothelial Function in Postmenopausal Women and Men: The Multi-Ethnic Study of Atherosclerosis.

Background: The relationship of endogenous sex hormones (SH) with vascular endothelial function and with cardiovascular disease (CVD) is incompletely understood. We examined the associations between SH and endothelial function measured by brachial artery flow-mediated dilation (FMD). Materials and Methods: We included 1368 postmenopausal women and 1707 men, free of clinical CVD, participating in MESA Visit 1 (2000-2002). Serum SH [total testosterone, SH binding globulin (SHBG), dehydroepiandrosterone (DHEA), estradiol] were measured; free testosterone was calculated. The percent FMD difference (%FMD) was measured by high-resolution ultrasound. Using multivariable-adjusted linear regression, we tested the cross-sectional associations of SH (log transformed, compared per one SD increment) with %FMD. Results: The mean age of women and men were 64.2 and 61.4 years, respectively. Among women, after adjusting for demographics, CVD risk factors, and hormone therapy, higher SHBG was associated with greater %FMD [β = 0.215% (95% CI 0.026-0.405)], whereas higher free testosterone was associated with a smaller %FMD [-0.209% (-0.402, -0.017)]. Estradiol and DHEA were not associated with %FMD in women after multivariable adjustment. There was an age interaction, with higher free testosterone and lower SHBG associated with worse FMD in women <65 years of age, but not in those ≥65 years (p = 0.04). We did not see similar associations in men. Conclusions: A more androgenic SH profile of higher free testosterone and lower SHBG was associated with worse %FMD in postmenopausal women. Changes in SH with aging and menopause may result in vascular changes in women. Further studies are needed to assess longitudinal changes in SH levels and their association with vascular function.

BH4 improves postprandial endothelial function after a high-fat meal in men and postmenopausal women

The timing and duration of menopause is important when evaluating the risk for cardiovascular disease in postmenopausal women, likely related in part to nitric oxide (NO) bioavailability. The flow-mediated dilation (FMD) test is a noninvasive assessment of NO bioavailability in humans, and tetrahydrobiopterin (BH4) is essential for NO synthesis. A high-fat meal (HFM) has been used to increase lipemia and reduce NO bioavailability. Thus, this study sought to determine if menopausal transition has any impact on the postprandial endothelial function response to a HFM, and evaluate the effect of BH4 on postprandial endothelial function in postmenopausal women and men. Utilizing a randomized, double-blind, placebo-controlled design, sex-steroid hormones and FMD were determined in 30 older adults (10 postmenopausal women aged below 3 y [W < 3], 10 postmenopausal women aged above 10 y [W > 10], and 10 men) at baseline and 4 hours after the ingestion of a HFM alone or a HFM with BH4 (HFM + BH4; 5 mg/kg). Data are presented as mean ± SEM. Independent of treatment, postprandial testosterone was significantly (P < 0.05) decreased in men (-64 ± 11 ng/dL), whereas no changes were observed in W < 3 or W > 10 group. In addition, concentrations of progesterone were higher (P = 0.019) and the testosterone/estradiol ratio was lower (P = 0.026) in all groups after the ingestion of HFM + BH4 compared with the ingestion of HFM alone. Overall, an increase in FMD was observed after the ingestion of HFM + BH4 (Δ1.9% ± 0.6%), whereas no change in FMD was observed after the ingestion of HFM alone (Δ-0.7% ± 0.6%). Co-ingestion of BH4 with a HFM not only alters the sex-steroid hormone ratio, it improves postprandial FMD after a HFM regardless of postmenopause status or sex.