Endothelial Function In Women Research Articles

The effect of acute estrogen suppression on cutaneous endothelium-dependent vasodilation in women with endometriosis

Cardiovascular disease risk is elevated in women with endometriosis and may be exacerbated by treatments that suppress estrogen. The purpose of this study was to determine the effects of acute estrogen suppression on endothelial function in women with endometriosis. We hypothesized that estrogen suppression would attenuate cutaneous endothelium-dependent vasodilation in endometriosis patients (ENDO; n = 2, 30 (1) y, 21.4 (0.2) kg·m2) but not in healthy controls (CON; n = 6, 28 (5) y, 24.9 (5.2) kg·m2). Trials were conducted with (POST) and without (PRE) 4 days of estrogen suppression (400 mg/day gonadotropin-releasing hormone antagonist, Elagolix®) during the first week of separate menstrual cycles. The cutaneous circulation was utilized as a model of microvascular vasodilatory function. Laser Doppler flowmetry was continuously measured during graded perfusions of acetylcholine through intradermal microdialysis (ACh, 1x10−10 – 1x10−1 M). Maximal vasodilation was elicited via 28 mM sodium nitroprusside perfusion and local heating (42°C). Cutaneous vascular conductance was calculated as LDF/mean arterial pressure (MAP). Dose response curves were generated with nonlinear modeling of normalized data with constraints and compared via median effective ACh dose (ED50) and HillSlope. Data are presented as mean (SD) and significance was set at α = 0.05. Baseline MAP was similar between trials for CON (PRE, 80.70 (6.32) mmHg; POST, 82.30 (5.37) mmHg; t[5] = -0.74, P = 0.49) and ENDO (PRE, 72.22 (0.31) mmHg; POST, 79.17 (7.31) mmHg; t[1] = -1.29, P = 0.42). ED50 was not impacted by estrogen suppression in CON (PRE, -3.61 (2.19) logM; POST, -2.80 (1.13) logM; t[5] = -1.04, P = 0.35) or ENDO (PRE, -3.08 (1.74); POST, -2.85 (0.68); t[1] = -0.13, P = 0.91). Similarly, HillSlope was not altered in CON (PRE, 1.00 (0.96); POST, 0.99 (1.14); t[5] = 0.01, P = 0.99) or ENDO (PRE, 0.81 (0.72); POST, 1.16 (1.15); t[1] = -0.26, P = 0.84). Acute estrogen suppression did not impact cutaneous endothelium-dependent vasodilation in healthy controls or women with endometriosis. A greater sample size will further evaluate this relationship. National Institutes of Health Grant 1R01HL161000. 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.

Antecubital venous endothelial ETB receptor protein expression is preserved with aging in men.

Changes in endothelial function precede the development of cardiovascular disease (CVD). We have previously shown that age-related declines in endothelial function in women are due in part to a reduction in endothelial cell endothelin-B receptor (ETBR) protein expression. However, it is not known if ETBR protein expression changes with aging in men. The purpose of this study was to test the hypothesis that ETBR protein expression is attenuated in older men (OM) compared with younger men (YM). Primary endothelial cells were harvested from the antecubital vein of 14 OM (60 ± 6 yr; 26 ± 3 kg/m2) and 17 YM (24 ± 5 yr; 24 ± 2 kg/m2). Cells were stained with 4',6-diamidino-2-phenylindole, vascular endothelial cadherin, and ETBR. Images were quantified using immunocytochemistry. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD). Systolic BP was similar (OM, 123 ± 11 vs. YM, 122 ± 10 mmHg) whereas diastolic BP was higher in OM (OM, 77 ± 7 vs. YM, 70 ± 6 mmHg; P < 0.01). Total testosterone was lower in OM (OM, 6.28 ± 4.21 vs. YM, 9.10 ± 2.68 ng/mL; P = 0.03). As expected, FMD was lower in OM (OM, 3.85 ± 1.51 vs. YM, 6.40 ± 2.68%; P < 0.01). However, ETBR protein expression was similar between OM and YM (OM, 0.39 ± 0.17 vs. YM, 0.42 ± 0.17 AU; P = 0.66). These data suggest that ETBR protein expression is not altered with age in men. These findings contrast with our previous data in women and further support sex differences in the endothelin system.NEW & NOTEWORTHY Our laboratory has previously shown that age-related declines in endothelial function are associated with a reduction in endothelial cell ETBR protein expression in women. However, it is unclear if endothelial cell ETBR protein expression is reduced with aging in men. This study demonstrates that endothelial cell ETBR protein expression is preserved with aging in men, and provides additional evidence for sex differences in the endothelin system.

Endogenous estradiol contributes to vascular endothelial dysfunction in premenopausal women with type 1 diabetes

BackgroundEndogenous estrogen is cardio-protective in healthy premenopausal women. Despite this favorable action of estrogen, animal models depict a detrimental effect of estradiol on vascular function in the presence of diabetes. The present study sought to determine the role of endogenous estradiol on endothelial function in women with type 1 diabetes.Method32 women with type 1 diabetes (HbA1c = 8.6 ± 1.7%) and 25 apparently healthy women (HbA1c = 5.2 ± 0.3%) participated. Flow-mediated dilation (FMD), a bioassay of nitric-oxide bioavailability and endothelial function was performed during menses (M) and the late follicular (LF) phase of the menstrual cycle to represent low and high concentrations of estrogen, respectively. In addition, a venous blood sample was collected at each visit to determine circulating concentrations of estradiol, thiobarbituric acid reactive substances (TBARS), and nitrate/nitrite (NOx), biomarkers of oxidative stress and nitric oxide, respectively. Data were collected in (1) 9 additional women with type 1 diabetes using oral hormonal birth control (HBC) (HbA1c = 8.3 ± 2.1%) during the placebo pill week and second active pill week, and (2) a subgroup of 9 demographically matched women with type 1 diabetes not using HBC (HbA1c = 8.9 ± 2.1%).ResultsOverall, estradiol was significantly increased during the LF phase compared to M in both type 1 diabetes (Δestradiol = 75 ± 86 pg/mL) and controls (Δestradiol = 71 ± 76 pg/mL); however, an increase in TBARS was only observed in patients with type 1 diabetes (ΔTBARS = 3 ± 13 µM) compared to controls (ΔTBARS = 0 ± 4 µM). FMD was similar (p = 0.406) between groups at M. In addition, FMD increased significantly from M to the LF phase in controls (p = 0.024), whereas a decrease was observed in type 1 diabetes. FMD was greater (p = 0.015) in patients using HBC compared to those not on HBC, independent of menstrual cycle phase.ConclusionEndogenous estradiol increases oxidative stress and contributes to endothelial dysfunction in women with diabetes. Additionally, HBC use appears to be beneficial to endothelial function in type 1 diabetes.

Functional Hypothalamic Amenorrhea and Preclinical Cardiovascular Disease.

Endothelial dysfunction is a preclinical cardiovascular disease (CVD) marker. Due to various neuroendocrine aberrations, functional hypothalamic amenorrhea (FHA) may be a sex-specific risk factor for CVD in young women. To investigate endothelial function in women with FHA, compared with eumenorrheic controls and recently menopausal women. We performed a cross-sectional analysis among women with FHA (n = 30), eumenorrheic controls (n = 29), and recently menopausal women (n = 30). FHA was defined as amenorrhea ≥3 consecutive months, estradiol <50 pg/mL, follicle-stimulating hormone (FSH) < 10 mIU/mL, and luteinizing hormone (LH) < 10 mIU/mL, excluding other etiologies. Participants were recruited through obstetrics and gynecology referrals, social media advertising, and review of electronic health records. Preclinical CVD was measured using EndoPAT 2000 to calculate reactive hyperemic index (RHI). RHI ≤1.67 indicates endothelial dysfunction. Mean estradiol levels in women with FHA, as compared with eumenorrheic controls and recently menopausal women, were 29.0 ± 18.1, 46.4 ± 15.7, and 10.9 ± 14.4 pg/mL (P < .0001), respectively. Women with FHA had lower insulin (P = .0095) and higher cortisol (P = .0004) compared with controls. RHI was significantly lower in women with FHA compared with eumenorrheic controls and recently menopausal women (1.8 ± 0.5 vs 2.2 ± 0.5 vs 2.2 ± 0.6, respectively; P = .008), and 35% of women with FHA had RHI ≤1.67, consistent with endothelial dysfunction. These results demonstrate endothelial dysfunction in 1 out of 3 young women with FHA. FHA may be a contributor to preclinical CVD, and it is not explained by hypoestrogenemia alone.

Effects of androgen excess and body mass index on endothelial function in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction; whether this is attributable to comorbid hyperandrogenism and/or obesity remains to be established. Therefore, we 1) compared endothelial function between lean and overweight/obese (OW/OB) women with and without androgen excess (AE)-PCOS and 2) examined androgens as potential modulators of endothelial function in these women. The flow-mediated dilation (FMD) test was applied in 14 women with AE-PCOS (lean: n = 7; OW/OB: n = 7) and 14 controls (CTRL; lean: n = 7, OW/OB: n = 7) at baseline (BSL) and following 7 days of ethinyl estradiol supplementation (EE; 30 µg/day) to assess the effect of a vasodilatory therapeutic on endothelial function; at each time point we assessed peak increases in diameter during reactive hyperemia (%FMD), shear rate, and low flow-mediated constriction (%LFMC). BSL %FMD was attenuated in lean AE-PCOS versus both lean CTRL (5.2 ± 1.5 vs. 10.3 ± 2.6%, P < 0.01) and OW/OB AE-PCOS (5.2 ± 1.5 vs. 6.6 ± 0.9%, P = 0.048). A negative correlation between BSL %FMD and free testosterone was observed in lean AE-PCOS only (R2 = 0.68, P = 0.02). EE increased %FMD in both OW/OB groups (CTRL: 7.6 ± 0.6 vs. 10.4 ± 2.5%, AE-PCOS: 6.6 ± 0.9 vs. 9.6 ± 1.7%, P < 0.01), had no impact on %FMD in lean AE-PCOS (5.17 ± 1.5 vs. 5.17 ± 1.1%, P = 0.99), and reduced %FMD in lean CTRL (10.3 ± 2.6 vs. 7.6 ± 1.2%, P = 0.03). Collectively, these data indicate that lean women with AE-PCOS exhibit more severe endothelial dysfunction than their OW/OB counterparts. Furthermore, endothelial dysfunction appears to be mediated by circulating androgens in lean but not in OW/OB AE-PCOS, suggesting a difference in the endothelial pathophysiology of AE-PCOS between these phenotypes.NEW & NOTEWORTHY We present evidence for marked endothelial dysfunction in lean women with androgen excess polycystic ovary syndrome (AE-PCOS) that is 1) associated with free testosterone levels, 2) impaired relative to overweight/obese women with AE-PCOS, and 3) unchanged following short-term ethinyl estradiol supplementation. These data indicate an important direct effect of androgens on the vascular system in women with AE-PCOS. Our data also suggest that the relationship between androgens and vascular health differs between phenotypes of AE-PCOS.

Effect of Oral Contraceptive Phase on Mechanisms of Cutaneous Microvascular Function

While the effect of oral contraceptive (OC) use on endothelial function has been previously studied, precise mechanisms of endothelial function in this group of women remains unclear. The purpose of this study was to investigate the contribution of cyclooxygenase (COX), endothelial‐derived hyperpolarizing factors (EDHF), and nitric oxide (NO) to cutaneous microvascular function in women during the low hormone (LH) and high hormone (HH) phases of OC. Five young, healthy women taking monophasic, combined OC of any generation visited the lab twice: once during the LH (d 1‐2 of placebo pills) and once during the HH phase (d 3‐6+ of active pills). Participants were instrumented with three microdialysis fibers, and each site was randomized as control (lactated Ringer's), COX inhibition (10 mM ketorolac), or EDHF inhibition (50 mM tetraethylammonium, TEA). Laser‐Doppler flowmetry and local heaters were used to measure skin blood flow and induce local thermal hyperemia, respectively. Each site was heated from 33°C to 39°C at a rate of 0.1°C/sec. Once a plateau to local heating was established, 20 mM L‐NAME, a NO synthase inhibitor, was infused at each site to quantify NO‐dependent vasodilation. Maximal vasodilation was induced by heating the skin to 43°C and infusing 28 mM sodium nitroprusside. Data are mean ± SD. For baseline, there was a main effect of OC phase (p = 0.03) and treatment (p &lt; 0.001) but no interaction effect (p = 0.21) such that baseline was increased at COX‐inhibited sites (23 ± 3 %CVCmax) compared with control (14 ± 6 %CVCmax; p = 0.03) during the HH phase. For initial peak, there was a main effect of treatment (p &lt; 0.001) but no effect of OC phase (p = 0.99) or interaction effect (p = 0.59) such that initial peak was decreased at EDHF‐inhibited sites during the HH phase (17 ± 6 %CVCmax) compared with control (51 ± 23 %CVCmax; p = 0.02). For local heating plateau, there was a main effect of treatment (p &lt; 0.001) but no effect of OC phase (p = 0.28) or interaction effect (p = 0.21) such that plateau was decreased at EDHF‐inhibited sites during both phases (LH: 18 ± 12 %CVCmax; HH: 20 ± 9 %CVCmax) compared with respective control (LH: 63 ± 13 %CVCmax; HH: 67 ± 23 %CVCmax) and ketorolac sites (LH: 58 ± 21 %CVCmax; HH: 71 ± 12 %CVCmax; all comparisons: p &lt; 0.01). For %NO, there was no observed effect of OC phase (p = 0.77), treatment (p = 0.21), or interaction (p = 0.09). While not statistically significant, there was a large effect size for %NO between LH and HH phases at control sites (LH: 72 ± 15 %NO; HH: 50 ± 23 %NO; Cohen’s d = 1.05). During the LH phase, large effect sizes were observed between control and TEA (48 ± 14 %NO; d = 1.65) sites and control and ketorolac (54 ± 22 %NO; d = 0.96) sites. During the HH phase, a large effect size was observed between control and ketorolac (69 ± 17 %NO; d = 0.94) sites. These preliminary data suggest mechanisms underlying endothelial function vary across OC phase in women. While overall endothelial function (i.e., magnitude of local heating plateau) is similar between OC phases, there may be basal constriction (i.e., increased baseline with COX inhibition) and reduced NO‐dependent dilation during the HH phase. This shift in mechanisms underlying endothelial function in women using OC may contribute to cardiovascular health outcomes.

Effect of Upright Posture on Endothelial Function in Women and Men.

Women are more prone to orthostatic intolerance compared to men and have a greater vasodilatory capacity. We investigated the hypothesis that women would have greater peripheral flow-mediated dilation (FMD) while in the upright posture compared to men, which could contribute to this phenomenon. In young healthy women (age: 20 ± 3, BMI: 27 ± 5 kg/m2, n = 10) and men (age = 21 ± 2, BMI: 27 ± 8 kg/m2, n = 8), we assessed FMD of the brachial artery and hemodynamics to determine endothelial function during the supine and 70° head-up tilt postures (randomized). The brachial artery was kept at heart level in both trials. We observed that FMD increased in both sexes during tilt (Women: 11.9 ± 5.3 to 15.7 ± 5.6%; Men: 8.4 ± 3.2 to 14.6 ± 3.4%, Main effect of tilt p = 0.005) which was not due to changes in blood pressure or shear stress. There were no interaction effects between sex and posture. In a second cohort of women (age: 22 ± 3, BMI: 23 ± 3 kg/m2, n = 9) and men (age: 22 ± 2, BMI: 25 ± 8 kg/m2, n = 8), we investigated reactive hyperemia by peripheral arterial tonometry (LnRHI) via EndoPAT. Interestingly, we found that the EndoPAT response was decreased in both sexes during tilt (LnRHI: Men: 0.70 ± 0.28 to 0.59 ± 0.40, Women: 0.52 ± 0.23 to 0.30 ± 0.32, Main effect of tilt p = 0.037). We previously found that FMD is related to coronary responses to acetylcholine and adenosine whereas EndoPAT is related to coronary responses to dobutamine. Therefore, we suggest that sympathetic mediated dilation is attenuated in the upright posture while the increased vasodilatory response as measured by FMD in the tilt posture could be attributed to increasing metabolite production from postural muscles.

Acute systemic inhibition of inflammation augments endothelium-dependent dilation in women with a history of preeclamptic pregnancy.

Women who have had preeclampsia demonstrate microvascular endothelial-dysfunction, mediated in part by reduced nitric oxide (NO)-dependent dilation. Preeclamptic pregnancies are associated with elevated inflammation, and inhibition of inflammation attenuates endothelial damage in animal models of preeclampsia. However, it is unclear if inhibition of vascular inflammation improves endothelial function in women after a preeclamptic pregnancy. Using the cutaneous microcirculation as a model, we hypothesized that acute systemic inhibition of vascular inflammation (oral salsalate; 1500mg/twice daily, 4days) would improve endothelium- and NO-dependent vasodilation in women with a history of preeclampsia (PE) but not in women with a history of uncomplicated pregnancy (HC). Twelve HC (30±1yrs, 10±2months postpartum) and 10 PE (30±2yrs, 8±2months postpartum) participated in a double-blind placebo-controlled study. Following each treatment, 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusion of acetylcholine (Ach, 10-7-102mM) or Ach+15mM L-NAME (NO synthase antagonist). Red blood cell flux was measured over each site by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC=LDF/mean arterial pressure) and normalized to maximum (%CVCmax; 28mM SNP+local heat 43°C). ACh-induced (77±3 vs. 92±3%CVCmax; p=0.01) and NO-dependent (20±6 vs. 33±4%; p=0.02) vasodilation were attenuated in PE compared to HC. Salsalate augmented ACh-induced (95±2%CVCmax; p=0.002) and NO-dependent (39±3%; p=0.009) dilation in PE compared to placebo but had no effect in HC (all p>0.05). Salsalate treatment augmented endothelium-dependent vasodilation via NO-mediated pathways in women who have had preeclampsia, suggesting that inflammatory signaling mediates persistent endothelial dysfunction following preeclampsia.

Reliability of Vasodilation in Response to Passive Leg Movement in Young, Healthy Women

Passive leg movement (PLM) elicits rapid vasodilation in the microvasculature that is primarily dependent on nitric oxide. PLM-induced vasodilation (PLM-D) therefore, provides an index of lower-limb microvascular endothelial function. PLM-D is lower in advanced aging and clinical populations vs. young and healthy controls, demonstrating that PLM-D provides a useful assessment of vascular responses. However, there is currently limited information regarding the reliability of PLM-D and no information on the reliability of PLM-D in women. Therefore, the purpose of this study was to test the hypothesis that PLM-D in women is reliable when measured over two separate days. Seventeen, young healthy women (22 ± 3 yrs) participated in two identical experimental visits during the early follicular (low-estrogen) phase of the menstrual cycle. Each visit included three standardized trials of PLM involving one minute of baseline, two minutes of PLM and two minutes of recovery. During the two minutes of PLM an experimenter moved the participant's leg from 90° flexion to 180° extension and back at a set pace of 1 cycle/s. Using duplex ultrasound PLM-D was characterized by six commonly utilized factors; peak leg blood flow (LBF) and vascular conductance (LVC), peak change above baseline (Δpeak) for LBF and LVC, and area under the curve above baseline (ΔAUC) during the first 60s of PLM for LBF and LVC. The day-to-day reliability of PLM-D was quantified by calculating the Pearson correlation coefficient (r value), intraclass correlation coefficient (ICC) and coefficient of variation (CV). The results demonstrated good day-to-day reliability of PLM-D characterized as peak LBF (r = 0.84, p < 0.001; ICC = 0.84; CV = 13.2%), peak LVC (r = 0.82, p < 0.001; ICC = 0.79; CV = 14.4%), Δpeak LBF (r = 0.83, p < 0.001; ICC = 0.82; CV = 17.8%) and Δpeak LVC (r = 0.83, p < 0.001; ICC = 0.80; CV = 16.5%). Characterization of PLM as ΔAUC demonstrated moderate day-to-day reliability; ΔAUC LBF (r = 0.71, p< 0.05; ICC = 0.70; CV = 31.2%) and ΔAUC LVC (r = 0.78, p < 0.001; ICC = 0.74; CV = 27.1%). In conclusion, this study demonstrates that PLM-D has good day-to-day reliability, however, characterization of PLM-D as peak and Δpeak LBF and LVC is more reliable than ΔAUC. These findings support the use of PLM-D in future studies as a reliable method to assess lower-limb microvascular endothelial function in women.

Abstract 15048: Ischaemic Pre-conditioning: A Non-invasive Intervention That Improves Maternal Endothelial Function in Women With Preeclampsia And at Risk of Preeclampsia

Introduction: Preeclampsia is a pregnancy syndrome defined by the gestational onset of hypertension and proteinuria and characterised by maternal endothelial dysfunction with placental ischaemia. Preeclampsia affects approximately 4% of first-time pregnant mothers, but approximately 20% of women with pre-existing hypertension. Ischaemic pre-conditioning (IPC) is a phenomenon whereby transient episodes of ischaemia protect against future ischaemic injury. IPC has never previously been studied in pregnant women. We investigated whether IPC could improve maternal endothelial function in women at risk of preeclampsia and with preeclampsia. Hypothesis: We hypothesised that IPC would improve maternal endothelial function in women with preeclampsia and at risk of preeclampsia. Methods: We measured brachial artery flow mediated dilatation (FMD), before and after IPC in 3 groups of pregnant women between 24+0 and 36+6 weeks gestation: normotensive pregnancy (n=42), at risk of preeclampsia (n=20) and established preeclampsia (n=11). Following a baseline measure of brachial artery FMD, 3 cycles of 5-minutes of upper arm ischaemia were alternated with 5-minutes of reperfusion. Twenty-four hours later, maternal FMD was re-measured. Results: Women with preeclampsia had the lowest baseline FMD 4.09% +/- 0.73%: mean +/- SEM, which increased to 6.25% +/- 0.83% (p=0.0024) following IPC. Women at risk of pre-eclampsia had baseline FMD 7.57% +/- 0.82%, which increased to 8.93% +/- 0.73% (p=0.025) following IPC. Normotensive pregnant women had the highest baseline FMD (10.32% +/- 0.69%), which did not increase further following IPC (10.52% +/- 0.69%). However, normotensive pregnant women reached peak flow-mediated dilatation more quickly following IPC; 414 s +/- 2.94 s v 425 s +/- 4.22 s (p=0.0302). Conclusions: IPC is a non-invasive technique that we have shown improves local endothelial function in women with preeclampsia and at risk of preeclampsia. IPC merits further study as an intervention to improve systemic endothelial function and pregnancy outcomes for women with hypertensive pregnancies.

Relationship between high-density lipoprotein cholesterol levels and endothelial function in women: a cross-sectional study

ObjectivesThe purpose of this study was to evaluate the relationship between high-density lipoprotein cholesterol (HDL-C) levels and endothelial function in women.DesignCross-sectional study.Setting22 university hospitals and affiliated clinics in Japan.Participants1719 Japanese...

Flt-1 And Endothelial Function Soon After Delivery: Effect Of Physical Activity

Vascular adverse pregnancy outcomes (APOs) are characterized by elevated levels of antiangiogenic Fms-like tyrosine kinase (Flt-1), attributable to placental ischemia. Flt-1 directly impairs endothelial function during pregnancy and contributes to maternal features of APOs, but infusion of Flt-1 into non-pregnant animals did not cause endothelial dysfunction. PURPOSE: The purpose was to evaluate the relation of Flt-1 and endothelial function in women 6 months – 3 years after delivery. Given the angiogenic effects of exercise, we tested the hypothesis that Flt-1 would be lower in women who achieved adequate prenatal and current physical activity (PA). METHODS: 40 nonsmoking women free from diabetes and use of protease inhibitors (mean age: 33±1 yrs, mean BMI: 26.3±1.0 kg/m2, 58% with adequate pregnancy PA) completed a blood draw and vascular testing after an overnight fast. We used an ELISA assay to determine levels of circulating Flt-1. Reactive hyperemia (RH) was measured with venous occlusion plethysmography to quantify resistance vessel endothelial function. A validated physical activity questionnaire (Godin Leisure Time Exercise Questionnaire) was used to determine current and second trimester PA; APO history was determined using self-report. We tested for associations of RH with continuous levels Flt-1 using linear regression, adjusted for APO status. We used t-tests to evaluate differences in Flt-1 between women who did versus did not achieve adequate PA during pregnancy or at the time of vascular testing. RESULTS: There was no association of Flt-1 and peak RH; β=0.01±0.01, p=0.50. There was no difference in Flt-1 levels between women who did versus did not achieve adequate PA at the time of testing (412±17 versus 443±31 pg/ml, p=0.22) or during pregnancy (408±20 versus 430±20 pg/ml, p=0.23). CONCLUSIONS: Although related to vascular dysfunction during pregnancy, Flt-1 was not related to vascular function after delivery and did differ by current or pregnancy PA level. Flt-1 might not be useful for identifying women at risk of vascular dysfunction after pregnancy ends.

The Effect of Low-Carbohydrate Diet on Macrovascular and Microvascular Endothelial Function is Not Affected by the Provision of Caloric Restriction in Women with Obesity: A Randomized Study.

Obesity impairs both macro- and microvascular endothelial function due to decreased bioavailability of nitric oxide. Current evidence on the effect of low-carbohydrate (LC) diet on endothelial function is conflicting and confounded by the provision of caloric restriction (CR). We tested the hypothesis that LC without CR diet, but not LC with CR diet, would improve macro- and microvascular endothelial function in women with obesity. Twenty-one healthy women with obesity (age: 33 ± 2 years, body mass index: 33.0 ± 0.6 kg/m2; mean ± SEM) were randomly assigned to receive either a LC diet (~10% carbohydrate calories) with CR (n = 12; 500 calorie/day deficit) or a LC diet without CR (n = 9) and completed the 6-week diet intervention. After the intervention, macrovascular endothelial function, measured as brachial artery flow-mediated dilation did not change (7.3 ± 0.9% to 8.0 ± 1.1%, p = 0.7). On the other hand, following the LC diet intervention, regardless of CR, blocking nitric oxide production decreased microvascular endothelial function, measured by arteriolar flow-induced dilation (p ≤ 0.02 for both diets) and the magnitude was more than baseline (p ≤ 0.04). These data suggest improved NO contributions following the intervention. In conclusion, a 6-week LC diet, regardless of CR, may improve microvascular, but not macrovascular endothelial function, via increasing bioavailability of nitric oxide in women with obesity.

MON-LB7 Assessment of Endothelial Dysfunction by Flow Mediated Dilation in Postmenopausal Women

Menopause is defined by the World Health Organization as the permanent cessation of menses as a result of the loss of ovarian follicular Function or surgical removal of ovary. Menopausal health demands priority in Indian scenario due to increase in life expectancy and growing population of menopausal women. It is well known that cardiovascular risk is higher in postmenopausal women than in premenopausal women, but it is unclear how much of the elevated risk is related to aging, menopause itself or presence of other confounding factors. Endothelial dysfunction is one of the most important predictors for determining early atherosclerotic risks as it precedes overt vascular disease by years and may itself be a potentially modifiable risk factor. Although no gold standard for the measurement of endothelial function exists, the measurement of flow mediated dilation (FMD) in the brachial artery, assessed with Doppler ultrasonography, is the most studied method and seems most promising for clinical application.objective - To compare effect of menopause on endothelial dysfunction by brachial artery flow mediated dilation (BAFMD) in postmenopausal women versus menstruating non-diabetic, non-obese females of same age group. Methodology: We conducted a case control study in Departments of Obstetrics & Gynaecology and Cardiology, PGIMER, Chandigarh.Subjects were menopausal women between 45- 55 years of age.Controls included the women of same age group who had not attained menopause.To detect a statistical significant difference of approximately 4-8% between cases and controls,50 women were recruited in both groups with a power of 90% and confidence interval of 95%. The study was approved by the ethics committee of the institute. Effect of menopause on BAFMD, NMD (nitro-glycerine mediated dilation), FRS (Framingham Risk score) and individual components of FRS was studied.Results: A statistically significant negative correlation was found between BAFMD and FRS, BAFMD and age and BAFMD and duration of menopause.On studying the effects of FRS, individual components of FRS and duration of menopause on smooth muscle function, statistically significant negative correlation was found between NMD and FRS and NMD and AgeConclusion:It was concluded that the menopausal status does not affect endothelial function in women who are at low risk of cardiovascular disease but it affects the vascular smooth muscle function. We also found significant correlation between FMD and NMD (p = 0.00) signifying that both endothelial dysfunction and vascular smooth muscle dysfunction are inter-related. On evaluating the strength of correlation of FMD with FRS, different parameters of FRS and duration of menopause, FMD was found to have a statistically significant negative correlation with all these parameters.

Acute Systemic Inhibition of Inflammation Augments Endothelium‐dependent Dilation in Women with a History of Preeclamptic Pregnancy

Women who have had preeclampsia demonstrate microvascular endothelial‐dysfunction, mediated in part by reduced nitric oxide (NO)‐dependent dilation. Preeclamptic pregnancies are associated with elevated inflammation, and inhibition of inflammation attenuates endothelial damage in animal models of preeclampsia. However, it is unclear if systemic inhibition of inflammation improves endothelial function in women after a preeclamptic pregnancy. Using the cutaneous microcirculation as a model, we hypothesized that acute systemic inhibition of inflammation (oral salsalate; 1500mg/twice daily/4 days) would improve endothelium‐ and NO‐dependent vasodilation in women with a history of preeclampsia (PrEC) but not in women with a history of uncomplicated pregnancy (HC). Eleven HC (30±1yrs, 9±2 months post‐partum) and 8 PrEC (29±3yrs, 6±1 months post‐partum) participated in a double‐blind placebo‐controlled study. Following each treatment, 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusion of acetylcholine (ACh, 10−7–102 mM) or ACh+15mM L‐NAME (NO synthase antagonist). Red cell flux was measured over each site by laser‐Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC=LDF/mean arterial pressure) and normalized to maximum (%CVCmax; 28mM SNP + local heat 43°C). ACh‐induced (75±3 vs. 92±4%CVCmax; p=0.002) and NO‐dependent (18±8 vs. 32±4%; p=0.04) vasodilation were attenuated in PrEC compared to HC following placebo. Salsalate augmented ACh‐induced (92±3%CVCmax; p=0.001) and NO‐dependent (38±4%; p=0.04) dilation in PrEC compared to placebo but had no effect in HC (all p&gt;0.05). Women who have had preeclampsia demonstrate attenuated microvascular endothelial function compared to women with a history of uncomplicated pregnancy. Salsalate treatment augmented endothelium‐dependent vasodilation via NO‐mediated pathways in these women, suggesting that inflammatory signaling plays a role in mediating persistent endothelial‐dysfunction in women with a history of preeclampsia. ClinicalTrials.gov registration # NCT03482440Support or Funding InformationNIH K99 HL138133 (Stanhewicz); NIH R01 HL093238 (Alexander); NIH T32 AG049676 (Serviente)

Comparison of the effects of endurance and endurance‑strength training programmes on the level of endothelial dysfunction in women with abdominal obesity: study protocol for a randomised controlled trial

The primary objective of the study is to compare the effect of endurance and endurance‑strength training on endothelial function in women with abdominal obesity. The secondary objectives include the assessment of the effect of both types of training on anthropometric, densitometric and biochemical parameters. In total, at least 100 women will be recruited for the study. The study population will be randomly divided into two groups according to the type of training: endurance and endurance‑strength training. During the 3-month of intervention, both groups will be performed three times a week training of an equal exercise volume and duration of 60 minutes. Before and after the intervention selected anthropometric and densitometric parameters will be measured and body composition will be analysed. In addition, biochemical parameters related to glucose and insulin homeostasis, lipid metabolism, antioxidant status, oxidative stress, inflammatory markers and endothelial function will be assessed.

Effect of Metformin on Microvascular Endothelial Function in Polycystic Ovary Syndrome

ObjectiveTo investigate the factors that are associated with the effect of metformin on endothelial dysfunction in polycystic ovary syndrome (PCOS). Patients and MethodsFrom March 24, 2014, to November 18, 2016, 48 women with PCOS were randomly assigned to 1500 mg/d of metformin (N=29) or no treatment (N=13) for 3 months; 42 patients (29 in the initial treatment group and 13 in the no treatment group) completed the study. Study variables were measured at baseline and after 3 months. Participants who did not receive metformin initially were then treated with metformin for another 3 months, and study variables were measured again. Endothelial function was measured as reactive hyperemia–peripheral arterial tonometry (RH-PAT) from the index finger. ResultsThe age and baseline endothelial function (mean ± SD) of the participants were 32.7±6.9 years and 1.8±0.5, respectively. No notable change was observed in endothelial function after 3 months with metformin compared with no treatment. However, after stratifying participants who received metformin based on baseline endothelial function, there was a significant improvement following metformin treatment in participants with abnormal baseline endothelial function (1.3±0.3 vs 1.7±0.3; P<.001) but not in those with normal baseline endothelial function (2.1±0.4 vs 2.0±0.5; P=.11). ConclusionMetformin improves endothelial function in women with PCOS and endothelial dysfunction independent of changes in glucose metabolism, dyslipidemia, or presence of prediabetes. Metformin has a direct effect on endothelial function in PCOS, and measurement of endothelial function can stratify and follow response to metformin treatment in PCOS. Trial Registrationclinicaltrials.gov Identifier: NCT02086526.

Effects of Endurance and Endurance-Strength Training on Endothelial Function in Women with Obesity: A Randomized Trial.

Some investigations have demonstrated that a combined endurance–strength training is the most effective in the treatment of obesity. The aim of the research was to access how different trainings influence: endothelial function, lipid metabolism, and risk of atherosclerosis in women with obesity. In a randomized trial, 39 obese women aged 28–62 completed endurance (n = 22, 60-80% HRmax) or combined training (n = 17, 20 minutes of strength exercises, 50–60% 1RM and 25 minutes of endurance training, 60-80% HRmax). Before and after the intervention vascular endothelial function (endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), thiobarbituric acid reactive substances (TBARS), blood total antioxidant capacity (TAC)), total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides and C-reactive protein (CRP)as well as visceral adiposity index (VAI), total-body skeletal muscle mass and atherogenic index of plasma (AIP) were determined. After the trainings, in both groups total cholesterol and total-body skeletal muscle mass increased (p < 0.05). In the group undergoing combined training, lower (p < 0.05) VAI, AIP, CRP and LDL-C were noted. In the group undergoing endurance training TBARS concentration decreased (p < 0.01), while the HDL-C (p < 0.01) concentration as well as eNOS (p < 0.05) activity increased. No significant differences between groups were found, either before or after the programs. Both training programs led to the improvement of lipid metabolism, but only endurance training alone favorably changed indicators of endothelial functions in women with obesity.

Local angiotensin-(1-7) administration improves microvascular endothelial function in women who have had preeclampsia.

Despite remission of clinical symptoms postpartum, women who have had preeclampsia demonstrate microvascular endothelial dysfunction, mediated in part by increased sensitivity to angiotensin II (ANG II). Angiotensin-(1-7) [Ang-(1-7)] is an endogenous inhibitor of the actions of ANG II and plausible druggable target in women who had preeclampsia. We therefore examined the therapeutic potential of Ang-(1-7) in the microvasculature of women with a history of preeclampsia (PrEC; n = 13) and parity-matched healthy control women (HC; n = 13) hypothesizing that administration of Ang-(1-7) would increase endothelium-dependent dilation and nitric oxide (NO)-dependent dilation and decrease ANG II-mediated constriction in PrEC. Using the cutaneous microcirculation, we assessed endothelium-dependent vasodilator function in response to graded infusion of acetylcholine (ACh; 10-7 to 102 mmol/L) in control sites and sites treated with 15 mmol/L NG-nitro-l-arginine methyl ester (l-NAME; NO-synthase inhibitor), 100 µmol/L Ang-(1-7), or 15 mmol/L l-NAME + 100 µmol/L Ang-(1-7). Vasoconstrictor function was measured in response to ANG II (10-20-10-4 mol/L) in control sites and sites treated with 100 µmol/L Ang-(1-7). PrEC had reduced endothelium-dependent dilation (P < 0.001) and NO-dependent dilation (P = 0.04 vs. HC). Ang-(1-7) coinfusion augmented endothelium-dependent dilation (P < 0.01) and NO-dependent dilation (P = 0.03) in PrEC but had no effect in HC. PrEC demonstrated augmented vasoconstrictor responses to ANG II (P < 0.01 vs. HC), which was attenuated by coinfusion of Ang-(1-7) (P < 0.001). Ang-(1-7) increased endothelium-dependent vasodilation via NO synthase-mediated pathways and attenuated ANG II-mediated constriction in women who have had preeclampsia, suggesting that Ang-(1-7) may be a viable therapeutic target for improved microvascular function in women who have had a preeclamptic pregnancy.

Aging women and their endothelium: probing the relative role of estrogen on vasodilator function.

Despite significant decreases in cardiovascular disease (CVD) mortality in the past three decades, it still remains the leading cause of death in women. Following menopause and the accompanying loss of estrogen, women experience a unique, accelerated rise in CVD risk factors. Dysfunction of the endothelium represents an important antecedent to CVD development, with rapid declines in endothelial vasodilator function reportedly taking place across the menopause transition. Importantly, the decline in endothelial function is independent of chronological age and is associated with estrogen deficiency. Estrogen-mediated effects, including increasing nitric oxide bioavailability and attenuating oxidative stress and inflammation, contribute to preserving endothelial health. This review will discuss studies that have probed the role of estrogen on endothelial vasodilator function in women at discrete stages of the menopause transition and the effects of estradiol supplementation in postmenopausal women. Estrogen receptor signaling is also an important aspect of endothelial function in women, and studies suggest that expression is reduced with both acute and prolonged estrogen deficiency. Changes in regulatory mechanisms of estrogen receptor-α expression as well as sensitivity to estrogen may underlie the differential effects of estrogen therapy in early (≤5 yr past final menstrual period) and late postmenopausal women (>5 yr past final menstrual period). Lastly, this review presents potential therapeutic targets that include increasing l-arginine bioavailability and estrogen receptor activation to prevent endothelial dysfunction in postmenopausal women as a strategy for decreasing CVD mortality in this high-risk population.