Vasodilation In Postmenopausal Women Research Articles

Effect of home-based heat therapy on 24-h blood pressure and cutaneous microvascular function in post-menopausal women with hypertension

Hypertension is a leading risk factor for cardiovascular morbidity and mortality and is often accompanied by microvascular dysfunction. Despite a clear effcacy in men, standard antihypertensive medications are less effective in post-menopausal women. Consequently, adjuvant therapies are needed to improve blood pressure control and microvascular function in post-menopausal women. Heat therapy may fill this therapeutic gap as it has been shown to reduce blood pressure and improve microvascular function in healthy and certain clinical populations. Therefore, the purpose of this study was to test the hypothesis that 8 weeks of home-based heat therapy would improve 24-h blood pressure and cutaneous nitric oxide-dependent vasodilation in post-menopausal women with hypertension. Post-menopausal women (69 ± 5 y) with hypertension were randomized to 8 weeks of sham ( N = 15) or heat therapy ( N = 13). Participants immersed their lower legs ~33 cm into a circulated and temperature-controlled (sham: 35 °C; heat therapy: 42 °C) water bath 4 days per week, and 45 min per session. Blood pressure and cutaneous microvascular function and were assessed before (pre) and after (post) the 8-week intervention. Mean arterial blood pressure was measured across 24-h using an ambulatory monitor. To assess microvascular function, an intradermal microdialysis probe was inserted in the anterior aspect of the lower leg at a site directly exposed to water (immersed) and at another site not directly exposed (non-immersed). Red blood cell flux was measured (laser doppler flowmetry) during cutaneous hyperemia induced by 39 °C local heating. N(G)-nitro-L-arginine methyl ester (L-NAME; 20mM) was then infused in each probe until a nadir in red blood cell flux was achieved. Cutaneous vascular conductance was calculated as red blood cell flux divided by mean arterial pressure and normalized to maximal vasodilation (42 °C heating + 56 mM sodium nitroprusside; CVC%max). Nitric oxide-dependent dilation was calculated as the difference between CVC%max measured during the 39 °C plateau and the L-NAME nadir. Mean arterial blood pressure did not differ across time or between groups (sham: pre, 96 ± 5 mmHg vs. post, 96 ± 6 mmHg; heat therapy: pre, 97 ± 4 mmHg vs. 99 ± 7 mmHg; P = 0.5 for interaction). Cutaneous vasodilation induced by local heating did not differ across time for either group (sham: pre, 60 ± 19 CVC%max vs. post, 64 ± 12 CVC%max; heat therapy: pre, 68 ± 15 CVC%max vs. post, 63 ± 13 CVC%max) or between immersed and non-immersed sites ( P = 0.9 for interaction). Similarly, nitric oxide-dependent vasodilation did not differ across time or between sites for either group ( P = 1.0 for interaction). Taken together, 8 weeks of home-based heat therapy does not improve blood pressure or cutaneous microvascular function in post-menopausal women with hypertension. This work was supported by grants from the National Institutes of Health (T32 AG020494; R01AG059314; F32HL167556) and the American Heart Association (TPA958179). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Nitric oxide contribution to endothelium-mediated vasodilation is attenuated in postmenopausal compared to premenopausal females

Background: Hypertension prevalence increases in females following menopause. Poor endothelial microvascular function increases risk of hypertension. Endothelial-mediated vasodilation is dependent on nitric oxide (NO). Estrogen enhances NO production; therefore, reduced estrogen levels in postmenopausal females may result in a reduced contribution of NO to endothelial-mediated vasodilation, although studies are limited. Herein, we aimed to investigate the contribution of NO to endothelial-mediated vasodilation in premenopausal and postmenopausal females. We hypothesized that postmenopausal females would have attenuated endothelium-mediated vasodilation and reduced contribution of NO compared to premenopausal females. Methods: Ten premenopausal (27±3 yrs) and eleven postmenopausal (59±4 yrs) normotensive females were studied. Resting brachial blood pressures were measured using a standard arm cuff. Brachial arterial catheters were placed for continuous blood pressure measurement and pharmacologic infusions. Forearm blood flow (FBF) was measured using venous occlusion plethysmography at baseline (saline) and during infusion of an endothelium-dependent vasodilator (acetylcholine; 1.0, 2.0, 4.0, and 8.0 μg/100mL tissue/min) with and without a NO synthase inhibitor (L-NG-monomethylarginine [L-NMMA]; 1.0 mg/min) co-infusion. Forearm vascular conductance (FVC) was calculated as FBF/mean arterial pressure✕100. Data were analyzed using a two-way repeated-measures ANOVA. Results: Resting systolic blood pressure (SBP) but not diastolic blood pressure (DBP) was greater in postmenopausal compared to premenopausal females (SBP: 121±15 vs. 103±9 mmHg, respectively; P<0.01; DBP: 72±11 vs. 65±5 mmHg, respectively; P=0.07). FBF responses to acetylcholine did not differ between premenopausal and postmenopausal females (Group Main Effect: P=0.11). When correcting for blood pressure, premenopausal females exhibited greater FVC responses to acetylcholine compared to postmenopausal females (Group Main Effect: P=0.04). In premenopausal females, FBF and FVC responses to acetylcholine were reduced with co-infusion of L-NMMA compared to acetylcholine infusion only (L-NMMA Main Effect: P=0.02 and P=0.01, respectively). In postmenopausal females, the FBF and FVC responses to acetylcholine were unaffected by L-NMMA (L-NMMA Main Effect: P=0.79 and P=0.76, respectively). Conclusion: Compared to premenopausal females, postmenopausal females have impaired endothelial microvascular function. Attenuated NO contribution during endothelium-mediated vasodilation in postmenopausal women may partially contribute to the increased hypertension risk in this population. AHA 14PRE18040000, AHA 898649, NIH HL083947, NIH HL148144, NCATS UL1 TR000135 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Effect of Short‐Term Estradiol Exposure on Endothelin‐B Receptor‐Mediated Vasodilation in Postmenopausal Women

Endothelin (ET)‐1 contributes to endothelial dysfunction in postmenopausal women (PMW) via the ETB receptor. We have previously shown that the ETB receptor mediates vasodilation in young women, an effect that is lost in PMW. However, it is unclear if ETB receptor‐mediated dilation can be restored in PMW exposed to E2.PURPOSETo test the hypothesis that E2 exposure restores ETB receptor‐mediated vasodilation in PMW.METHODSWe tested 9 PMW (55±2 yrs, 24±3 kg/m2, 91±5 mmHg) who self‐reported natural menopause and were at least 1 year without menses. We measured vasodilation in the cutaneous microcirculation via local heating using laser Doppler flowmetry coupled with intradermal microdialysis during perfusions of lactated Ringer’s (control), ETB receptor antagonist (BQ‐788, 300nM) and ETA receptor antagonist (BQ‐123, 500nM). Cutaneous vascular conductance (CVC) was calculated during the plateau phase of local heating (42°C), and normalized to maximal vasodilation achieved by perfusion of sodium nitroprusside (28mM) and heating to 43°C. All women were tested at baseline (BL) and after 7 days of E2 (Vivelle‐Dot, 0.1mg/day, transdermal patch) administration (+E2). A two‐way repeated measures ANOVA was performed to compare %CVCmax in PMW before and after E2 exposure. Data presented are mean ± standard deviation.RESULTSE2 administration increased serum estradiol (BL: 45±29 vs +E2: 71±42 pg/mL, P&lt;0.01) and reduced follicle stimulating hormone (BL: 71±13 vs +E2: 57±17 pg/mL, P&lt;0.01), but there were no changes in serum progesterone (BL: 0.57±0.93 vs +E2: 0.53±0.88 pg/mL, P=0.14) nor plasma ET‐1 (BL: 1.62±0.66 vs +E2: 1.54±0.54 pg/mL, P=0.42). E2 administration had no effect on cutaneous microvascular responses (Time P=0.41, Drug P=0.17, Interaction P=0.71). At BL, vasodilatory responses to local heating were not different during control and ETB receptor antagonism (control: 83±8 vs. BQ‐788: 88±6 %CVCmax). Similarly, vasodilation was not altered at BL during ETA receptor antagonism in a subset of women (n=6, control: 83±8 vs. BQ‐123: 87±8 %CVCmax). E2 administration did not improve vasodilation in the control site (BL: 83±8 vs. +E2 85±13 %CVCmax). Furthermore, there was no effect of E2 exposure on cutaneous vasodilatory responses during perfusion of ETB (BL: 88±6 vs. +E2: 89±6 %CVCmax) nor ETA (n=6, BL: 87±8 vs +E2: 92±7 %CVCmax) receptor antagonists.CONCLUSIONThese preliminary data suggest that short‐term E2 exposure does not modulate ETB receptor function in PMW. These findings are in contrast to our observations in young women demonstrating that ETB receptors mediate vasodilation in the presence of E2. The role of alternative therapies to modulate ETB receptor function should be considered in future studies.

Abstract P095: Aerobic Exercise Training Reduces Endothelin-1-mediated Vasoconstriction In Postmenopausal Women

Endothelin-1 (ET-1)-mediated vasoconstrictor tone is elevated in postmenopausal women (PMW), contributing to their increased cardiovascular risk. Although aerobic exercise is beneficial in reducing ET-1 system activity in men, it is unknown whether this favorable vascular effect is conferred in women. In fact, contrary to men, it is uncertain whether aerobic exercise training improves endothelial dysfunction in PMW. We tested the hypothesis that aerobic exercise training reduces ET-1-mediated vasoconstriction in PMW. We further hypothesized reductions in ET-1 vasoconstrictor tone underly exercise-induced improvements in endothelium-dependent vasodilatation in PMW. Methods: Forearm blood flow (FBF) responses to intra-arterial infusion of selective ET A receptor blockade (BQ-123, 100 nmol/min for 60 min), acetylcholine (4.0, 8.0 and 16.0 μg/100 mL tissue/min) in the absence and presence of ET A receptor blockade and sodium nitroprusside (1.0, 2.0 and 4.0 μg/100 mL tissue/min) were determined before and after a 12-week aerobic exercise training intervention in 20 healthy, sedentary PMW (56 + 1 yr). Results: All 20 PMW completed the exercise intervention, walking an average of 4.9 + 0.1 d/wk for 50 + 2 min/d at 71 + 1% of maximal heart rate. After the exercise intervention, BQ-123 elicited no significant change in resting FBF in the previously sedentary PMW compared with significant vasodilation (~25%) before exercise. FBF responses to acetylcholine were markedly higher (~25%; P&lt;0.05) after (from 4.3 + 0.3 to 13.8 + 0.8 mL/100 ml tissue/min) vs before (from 4.1 + 0.2 to 11.3 + 0.8 mL/100 ml tissue/min) exercise training. Moreover, before exercise training the co-infusion of BQ-123 with acetylcholine enhanced (~25%; P&lt;0.05) the vasodilator response (from 4.3 + 0.3 to 13.7 + 0.7 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. Conclusions: These data demonstrate that 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.

Acute Estrogen Does Not Augment the β2 ‐ Adrenergic Receptor Mediated Vasodilation in Postmenopausal Women

IntroductionAcute estrogen infusion augments β2 ‐adrenergic receptor responsiveness in premenopausal women. This suggests an influential role of estrogen in controlling the vasodilator responsiveness via β2 ‐adrenergic receptors in premenopausal women. Postmenopausal women present with a reduced β2 ‐adrenergic receptor responsiveness as compared to premenopausal women. This divergent finding in β2 ‐adrenergic receptor responsiveness could be due to loss of endogenous estrogen postmenopause.ObjectiveHence, the objective of the study was to compare the β2 ‐adrenergic vasodilator responses with and without estrogen in postmenopausal women. We hypothesized that the vasodilator effects during endothelial dependent, independent and during β2 ‐adrenergic agonist infusion would be significantly greater with acute, local estrogen administration.MethodsVenous occlusion plethysmography was used to measure forearm blood flow (FBF) in 8 older (age = 59 ± 1 years) healthy, non‐obese (BMI = 23 ± 1 kg/m2) women. FBF was measured at baseline and during an intra‐arterial infusion of acetylecholine (ACH) at 1.0, 2.0, 4.0, and 8.0 μg/100 ml tissue/min, sodium nitroprusside (NTP) at 0.25, 0.5, 1.0 and 2.0 ug/100 ml tissue/min and terbutaline (β2 agonist) at 0.1, 0.5, 1.0, 2.0 μg/100 ml tissue/min before (with dextrose co‐infusion) and during acute, local intra‐arterial infusion of estrogen (20 ηg/mL at 1 mL/min). Forearm vascular conductance (FVC) was calculated as FBF divided by mean arterial pressure. Area under the curve (AUC) was calculated for the absolute FVC and percent baseline FVC of ACH, NTP and terbutaline.ResultsThere were no significant differences in FVC with estrogen infusion as compared to control during ACH, NTP and all terbutaline doses except dose 2 of ACH (Table 1). The AUC are not significantly different during estrogen (p&gt;0.05) as compared to control for ACH, NTP and terbutaline (figure 1).ConclusionsThese data suggest that acute administration of estrogen, which corresponds to the endogenous levels of estrogen seen in premenopausal women during mid‐cycle, does not augment the β2 ‐adrenergic vasodilator responses in postmenopausal women. Additionally, these data suggest that estrogen infusion does not increase the endothelial dependent and independent vasodilatory capacity in postmenopausal women.Support or Funding InformationHL83947 (MJJ) and Mayo Clinic Women's Health Scholarship (K12 HD065987).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

ETB receptor contribution to vascular dysfunction in postmenopausal women.

Endothelin-1 (ET-1) contributes to age-related endothelial dysfunction in men via the ETA receptor. However, there are sex differences in the ET-1 system, and ETB receptors are modulated by sex hormones. The purpose of this study was to test the hypothesis that ETB receptors contribute to impaired vasodilatory function in postmenopausal women (PMW). We measured flow-mediated dilation (FMD) using ultrasound, and cutaneous nitric oxide-mediated vasodilation during local heating (42°C) via laser Doppler flowmetry in 18 young women (YW; 22 ± 1 yr) and 16 PMW (56 ± 1 yr). Cutaneous microdialysis perfusions of lactated Ringer (control), an ETB receptor antagonist (BQ-788, 300 nM), and an ETA receptor antagonist (BQ-123, 500 nM), were done through separate fibers, followed by perfusions of sodium nitroprusside (28 mM) and local heating to 43°C (max). Cutaneous vascular conductance (CVC) was calculated as cutaneous blood flow/mean arterial pressure and expressed as a percent of maximal dilation. FMD (YW: 7.5 ± 0.5 vs. PMW: 5.6 ± 0.6%) and cutaneous vasodilation (YW: 93 ± 2 vs. PMW: 83 ± 4%CVCmax) were lower in PMW (both P < 0.05). Blockade of ETB receptors decreased cutaneous vasodilation in YW (87 ± 2%CVCmax; P < 0.05 vs. control) but increased vasodilation in PMW (93 ± 1%CVCmax; P < 0.05 vs. control). ETA receptor blockade had minimal effect in YW (92 ± 1%CVCmax) but increased cutaneous vasodilation in PMW (91 ± 2%CVCmax; P < 0.05 vs. control). In conclusion, ETB receptors mediate vasodilation in YW, but this effect is lost after menopause. Impaired vasodilatory function in PMW is due in part to a loss of ETB-mediated dilation.

Role of nitric oxide in β2-adrenergic mediated vasodilation in postmenopausal women

Role of nitric oxide in β2-adrenergic mediated vasodilation in postmenopausal women

Endothelin‐B Receptor Responses in Young and Postmenopausal Women

Cardiovascular disease (CVD) is the leading cause of the death in women, and postmenopausal women (PMW) are at an increased risk for developing CVD. Endothelin‐1 (ET‐1) contributes to age‐related endothelial dysfunction in men via the ETA receptor. However, there are sex differences in ET‐1 regulation of vascular function, and ETB receptors are influenced by fluctuations in ovarian hormones.PURPOSEThe purpose of this study was to test the hypothesis that ETB receptors contribute to impaired microvascular function in PMW.METHODSWe measured skin blood flow (SkBF) in 11 young women (YW; 22±1 years, 22±1 kg/m2) and 10 PMW (58±2 years, 24±1 kg/m2) using laser Doppler flowmetry during microdialysis perfusions of lactated Ringer's (control), an ETB receptor antagonist (BQ‐788, 300nM), and an ETA receptor antagonist (BQ‐123, 500 nM). We utilized local skin heating (42°C) to induce microvascular vasodilation, followed by perfusion of sodium nitroprusside (28mM) to elicit maximal dilation. Mean arterial blood pressure (MAP) was measured throughout. Cutaneous vascular conductance (CVC) was calculated as SkBF/MAP during the plateau established during local heating, and expressed as a percent of maximal dilation. Unpaired t‐tests were used to compare variables between YW and PMW.RESULTSResting MAP was higher in PMW (93±2 mmHg) compared to YW (80±2 mmHg; P&lt;0.05). Vasodilatory responses to local heating (control site) tended to be lower in PMW (YW: 91±2 vs. PMW: 81±5 CVC % max; P=0.12). ETB receptor blockade tended to decrease cutaneous vasodilation in YW (control: 91±2 vs. BQ‐788: 85±3 CVC % max; P=0.08), but tended to enhanced vasodilation in PMW (control: 81±5 vs. BQ‐788: 92±1 CVC % max; P=0.08). ETA receptor blockade had minimal effect in YW (control: 91±2 vs. BQ‐123: 92±2 CVC % max; P=0.35), but tended to increase cutaneous vasodilation in PMW (control: 81±5 vs. BQ‐123: 90±2 CVC % max; P=0.11).CONCLUSIONETB receptors appear to mediate vasodilation in YW. However, microvascular vasodilation is blunted in PMW, possibly due to greater ETB and ETA mediated vasoconstriction.Support or Funding InformationSupported by NIH Grant U54 GM 104941 01A1 and University of Delaware Research Foundation.

198 The Impact of Menopause and Oestrogen Replacement Therapy on Cardioprotection in Remote Ischaemic Preconditioning

IntroductionRemote ischaemic preconditioning (rIPC) is postulated to involve the generation of a humoral signal possibly involving an endothelial signalling pathway. Our lab and others have demonstrated the cardioprotective effects of...

Genistein and endothelial function in postmenopausal women with metabolic syndrome

Previous data have suggested that genistein could exert beneficial effects on endothelial function and on predictors of cardiovascular risk in healthy postmenopausal women. In a randomized clinical trial, we studied the effects of genistein on endothelial function in postmenopausal women with metabolic syndrome (MS). Twenty postmenopausal women with MS, according to modified NCEP-ATP III criteria were randomly assigned to receive placebo or genistein (54 mg/day) for 6 months, along with a Mediterranean-style diet. Postmenopausal women without MS (n = 15), served as controls. The primary goal was the assessment of endothelial function by flow-mediated vasodilation (FMD) of brachial artery; moreover, time-to-peak dilation in the FMD response has been evaluated. Secondary outcomes were fasting glucose, fasting insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, visfatin, adiponectin and homocysteine blood levels. Data on adverse events were also recorded. After 6 months of treatment, FMD at 50s and peak FMD significantly increased in genistein recipients compared with placebo. Moreover, genistein significantly decreased the blood levels of total cholesterol, triglycerides, homocysteine and visfatin compared with placebo, while blood adiponectin levels were increased. Genistein recipients neither experienced more side-adverse effects than placebo nor discontinued the study. Six months of treatment with genistein effectively improves brachial artery flow-mediated vasodilation in postmenopausal women with metabolic syndrome.

Role of glucocorticoid receptor in the inhibitory effect of medroxyprogesterone acetate on the estrogen-induced endothelial nitric oxide synthase phosphorylation in human umbilical vein endothelial cells

We aimed to clarify which steroid receptor is involved in the inhibitory effect of medroxyprogesterone acetate (MPA) on estrogen-induced endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells (HUVEC). The progesterone/glucocorticoid receptor (GR) antagonist RU-486 and introduction of GR siRNA caused attenuation of the inhibitory effect of MPA on the estrogen-induced eNOS phosphorylation and eNOS activity in HUVEC.

A Meal Enriched with Soy Isoflavones Increases Nitric Oxide-Mediated Vasodilation in Healthy Postmenopausal Women

Evidence from infusion studies suggests that soy isoflavones influence nitric oxide-dependent vasorelaxation. It is uncertain whether orally consumed isoflavones have similar effects. Healthy postmenopausal women (n = 22) consumed 2 low-fat test meals in random order 1 wk apart, with 80 mg isoflavones (ISO) or without isoflavones (CON). Endothelium-dependent vasodilation, assessed by brachial artery flow-mediated dilatation (FMD), was measured in fasting subjects, and 4 and 6 h following the test meal, in addition to blood pressure and pulse wave analysis to derive the peripheral augmentation index (pAIx). Blood samples were taken after fasting, and 5 and 7 h following the test meal for serum isoflavone, plasma 8-isoprostane F2 α, nitric oxide metabolites (NOx), glucose, and triacylglycerol analysis. Serum genistein and daidzein concentrations (geometric mean, 95% CI) reached 1.49 (1.20–1.84) μmol/L and 0.95 (0.70–1.30) μmol/L, respectively, following ISO (7 h). FMD and plasma NOx concentrations were greater following ISO compared with CON, indicating better postprandial endothelial function. FMD values (%, mean ± SD) were: CON, 5.49 ± 2.32, 4.35 ± 2.32, 4.40 ± 2.26; ISO, 5.38 ± 1.91, 5.08 ± 1.74, 6.11 ± 2.60, at baseline, 4 h, and 6 h, respectively (P < 0.01). Plasma NOx concentrations (μmol/L, mean ± SD) were: CON, 20.0 ± 5.1, 16.8 ± 5.1, 23.1 ± 6.0; ISO, 18.6 ± 6.3, 19.5 ± 5.1, 21.3 ± 10.1, at baseline, 5 h, and 7 h, respectively (P < 0.005). Treatment did not affect pAIx, blood pressure, or plasma 8-isoprostane F2 α concentrations. In conclusion, consuming an isoflavone-enriched low-fat meal acutely increases endothelium-dependent vasodilation in postmenopausal women. Regular consumption of soy isoflavones may protect against endothelial dysfunction.

HRT restores exercise capacity and flow-mediated vasodilation in postmenopausal women

HRT restores exercise capacity and flow-mediated vasodilation in postmenopausal women

Impaired Endothelium-Dependent and -Independent Vasodilation in Young Female Athletes With Exercise-Associated Amenorrhea

To the Editor: Estrogen has great roles in controlling vascular function.1 Especially, estrogen augments endothelium-dependent vasodilation by increasing the bioavailability of endothelium-derived nitric oxide.2 Not only does estrogen replacement improve endothelium-dependent vasodilation in postmenopausal women,3 but also endothelium-dependent vasodilation is enhanced by endogenous estradiol during the menstrual cycle in women.4 Exercise-associated amenorrhea (EAA) is observed in highly-trained female athletes.5 Although physical exercise training usually improves vascular function in subjects with cardiovascular risk factors,6 it is unknown whether such strenuous sport activity that causes amenorrhea affects vascular function. Flow-mediated vasodilation (FMD) during reactive hyperemia can be quantitated as an index of endothelium-dependent vascular function.7 FMD was shown to be reduced in amenorrheic athletes,8 however it was unclear whether the abnormality of FMD was related to estrogen levels. Accordingly, we investigated vascular function in young highly trained athletes with and without EAA, and measured endogenous ovarian hormones to explore the underlying mechanisms of endothelial dysfunction in amenorrheic athletes. We also examined whether vascular function was restored by the recovery of the regular menstrual cycle after quitting competitive sport activity. We enrolled 26 young female highly-trained volleyball players (mean age, 16.4 years) including athletes with a regular menstrual cycle (RMC; n=14) and those with EAA (n=12). Age-matched female non-athletes with a regular menstrual cycle were enrolled as controls (n=10). The players participated regularly in exercise training 6 days a week and …

Exercise as an alternative to oral estrogen for amelioration of endothelial dysfunction in postmenopausal women

Both exercise and postmenopausal estrogen therapy augment endothelial function. We hypothesized that their interaction would be additive. The study objectives were to determine in postmenopausal women (1) the effects of an acute bout of exercise on brachial artery endothelium-dependent flow-mediated vasodilation (FMD), (2) whether these responses to exercise are augmented by concurrent estrogen treatment, and (3) whether these 2 interventions, independently or together, achieve FMD values observed in premenopausal women. In postmenopausal women (n = 13; age 54 +/- 2 [mean +/- SE] years), FMD was quantified during supine rest and again 60 minutes after treadmill exercise for 45 minutes at 60% V* O2max. Subjects were studied twice: before and after 4 weeks of oral estradiol. To obtain reference normal values, FMD was determined concurrently in 14 premenopausal (28 +/- 1 years) women under identical basal conditions. Flow-mediated vasodilation in postmenopausal women, markedly impaired when compared with premenopausal women (5.3% +/- 0.5% vs 12.1% +/- 1.5%, P < .01), was significantly increased by exercise (to 9.9% +/- 0.6%, P < .01). In contrast, after estrogen, FMD was augmented at rest (P < .01) but was not further enhanced after exercise (11.5% +/- 0.6% vs 9.9% +/- 0.5%, P = .3). Both interventions increased, independently, FMD to values in premenopausal women (P > .05). In postmenopausal women, both acute exercise and estrogen therapy normalize FMD. However, their effects are not additive, possibly because of redundancy of nitric oxide signaling pathways activated by these 2 interventions. When considered in the context of recent trials with adverse cardiovascular outcomes, these results reinforce the therapeutic potential of exercise as an alternative nonpharmacological intervention to estrogen in postmenopausal women with endothelial dysfunction.

Small low-density lipoprotein particles and endothelium-dependent vasodilation in postmenopausal women

Low concentrations of estrogen may decrease endothelial function in postmenopausal women. Elevated plasma triglycerides after menopause are frequently associated with a small, dense low-density lipoprotein (LDL) phenotype. Small LDL particles that are more susceptible to oxidation can also inhibit endothelium-dependent vasodilation. The purpose of the present study was to investigate whether hypertriglyceridemia-induced small LDL particles are associated with endothelial dysfunction in postmenopausal women. We studied 15 premenopausal and 41 postmenopausal women. Postmenopausal subjects were divided into those with LDL subclass pattern A (large particles) and those with pattern B (small particles). Plasma lipids, hormones, and diameter and oxidative susceptibility of LDL were measured. Vasodilatory responses of the brachial artery were evaluated by measuring flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation (NID). FMD in both postmenopausal groups was significantly lower than in premenopausal women. FMD in subjects with pattern B was significantly smaller than in those with pattern A (4.9 ± 1.9% versus 8.8 ± 3.6%). NID did not differ significantly among the groups. Plasma triglyceride concentrations were higher, lag time for LDL oxidation was shortened, and LDL-derived thiobarbituric acid-reactive substance (TBARS) concentrations were significantly greater in subjects with pattern B than in premenopausal or pattern A subjects. LDL diameter correlated negatively with plasma triglycerides ( r = −0.51) or LDL-derived TBARS ( r = −0.44) and positively with LDL-lag time ( r = 0.66). FMD correlated negatively with LDL-derived TBARS ( r = −0.36) and positively with LDL diameter ( r = 0.44) or LDL-lag time ( r = 0.43). Vascular endothelial dysfunction may be associated with elevated triglyceride-induced small LDL particles that have enhanced oxidative susceptibility in postmenopausal women.

Cardiovascular effects of the phytoestrogen genistein.

Phytoestrogenic molecules have received a great deal of attention over the last few years because of their potentially preventive roles against a few of today's most prevalent chronic diseases, namely cardiovascular diseases, osteoporosis and hormone related cancers. Of the several phytoestrogens, genistein in particular has been shown to be the most efficacious in animal models and experimental studies. Genistein in vitro relaxes rat arteries by a nitric oxide dependent mechanism and enhances the dilator response to acetylcholine of atherosclerotic arteries. Genistein supplementation improves endothelial dysfunction induced by oophorectomy in rats and reduces infarct size in an experimental model of myocardial ischaemia-reperfusion injury. Furthermore, genistein in postmenopausal women increases plasma nitric oxide breakdown products, reduces endothelin-1 levels and improves endothelial dependent vasodilation in post-menopausal women. All these findings, taken together, would suggest that this molecule might represent an attractive alternative for cardiovascular protection.

Effects of raloxifene on carotid blood flow resistance and endothelium-dependent vasodilation in postmenopausal women

Raloxifene is one of the most important selective estrogen receptor modulators currently employed for the treatment of postmenopausal osteoporosis. However, it has also been suggested that this compound affects the vascular system. We evaluated both carotid blood flow resistance and endothelium-dependent vasodilation in 50 healthy postmenopausal women randomly assigned to receive, in a double blind design, either raloxifene (60 mg per day; N=25 subjects) or placebo ( N=25 subjects) for 4 months. Indices of carotid blood flow resistance, such as the pulsatility index (PI) and resistance index (RI), as well as the flow-mediated brachial artery dilation were measured both at baseline and at the end of treatment. Changes in PI were −1.86±2.24 and −2.15±2.22% after placebo and raloxifene treatment, respectively, with no significant differences between groups. Changes in RI were −0.77±1.72 and −1.81±1.54% after placebo and raloxifene treatment, respectively, with no significant differences between groups. At the end of the treatment period, the increments in artery diameter measured after the flow stimulus were 10.79±2.39 and 6.70±1.23% for placebo and raloxifene, respectively, with no significant differences between groups. These results demonstrate no significant effects of raloxifene on either carotid blood flow resistance or brachial artery flow-mediated dilation in postmenopausal women.