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.

ETB receptor-mediated vasodilation is regulated by estradiol in young women.

The endothelin-B (ETB) receptor is a key regulator of vascular endothelial function in women. We have previously shown that the ETB receptor mediates vasodilation in young women, an effect that is lost after menopause. However, the direct impact of changes in estradiol (E2) on ETB receptor function in women remains unclear. Therefore, the purpose of this study was to test the hypothesis that E2 exposure modulates ETB receptor-mediated dilation in young women. Fifteen young women (24 ± 4 yr, 24 ± 3 kg/m2) completed the 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 vasodilation in the cutaneous microcirculation (microvascular endothelial function) via local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant + E2) using laser Doppler flowmetry coupled with intradermal microdialysis during perfusions of lactated Ringer's (control) and ETB receptor antagonist (BQ-788, 300 nM). During GnRHant, vasodilatory responses to local heating were enhanced with ETB receptor blockade (control: 83 ± 9 vs. BQ-788: 90 ± 5%CVCmax, P = 0.004). E2 administration improved vasodilation in the control site (GnRHant: 83 ± 9 vs. GnRHant + E2: 89 ± 8%CVCmax, P = 0.036). Furthermore, cutaneous vasodilatory responses during ETB receptor blockade were blunted after E2 administration (control: 89 ± 8 vs. BQ-788: 84 ± 8%CVCmax, P = 0.047). These data demonstrate that ovarian hormones, specifically E2, modulate ETB receptor function and contribute to the regulation of microvascular endothelial function in young women.NEW & NOTEWORTHY The endothelin-B (ETB) receptor mediates vasodilation in young women, an effect lost following menopause. It is unclear whether these alterations are due to aging or changes in estradiol (E2). During endogenous hormone suppression (GnRH antagonist), blockade of ETB receptors enhanced cutaneous microvascular vasodilation. However, during E2 administration, blockade of ETB receptors attenuated vasodilation, indicating that the ETB receptor mediates dilation in the presence of E2. In young women, ETB receptors mediate vasodilation in the presence of E2, an effect that is lost when E2 is suppressed.

ET-1 as a Sex-Specific Mechanism Impacting Age-Related Changes in Vascular Function.

Aging is a primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in developed countries. Globally, the population of adults over the age of 60 is expected to double by the year 2050. CVD prevalence and mortality rates differ between men and women as they age in part due to sex-specific mechanisms impacting the biological processes of aging. Measures of vascular function offer key insights into cardiovascular health. Changes in vascular function precede changes in CVD prevalence rates in men and women and with aging. A key mechanism underlying these changes in vascular function is the endothelin (ET) system. Studies have demonstrated sex and sex hormone effects on endothelin-1 (ET-1), and its receptors ETA and ETB. However, with aging there is a dysregulation of this system resulting in an imbalance between vasodilation and vasoconstriction. Thus, ET-1 may play a role in the sex differences observed with vascular aging. While most research has been conducted in pre-clinical animal models, we describe more recent translational data in humans showing that the ET system is an important regulator of vascular dysfunction with aging and acts through sex-specific ET receptor mechanisms. In this review, we present translational evidence (cell, tissue, animal, and human) that the ET system is a key mechanism regulating sex-specific changes in vascular function with aging, along with therapeutic interventions to reduce ET-mediated vascular dysfunction associated with aging. More knowledge on the factors responsible for the sex differences with vascular aging allow for optimized therapeutic strategies to attenuate CVD risk in the expanding aging population.

Patterns of Home Environmental Modification Use and Functional Health: The Women's Health Initiative.

BACKGROUND: We examined common patterns of home environmental modification (HEM) use and associated major (including disability-, cardiovascular-, and cancer-related) health conditions and events among older women. METHODS: Women, aged 78.6 ±â€…6.3 years (n = 71,257), self-reported utilization of nine types of HEMs (hand rails, grab bars, ramps, nonslip surfaces, tacking carpets/rugs, decreasing clutter, increasing lighting, raised sink/counter heights, other). Concurrent history of major health conditions and events was collected. Odds ratios (ORs) were estimated based on overall HEM use and four latent classes (low HEM use [56%], rails/grab bars [20%], lighting/decluttering [18%], high HEM use [5%]), adjusted for age, marital status, race/ethnicity, education, depression, and obesity. RESULTS: Fifty-five percent of women reported using any HEM (overall), with strongest associations among disability-related conditions. Activities of daily living limitations were strongly associated with high HEM use (OR = 8.16, 95% confidence interval [CI] = 6.62-10.05), railing/grab bar use (OR = 4.02, 95% CI = 3.26-4.95), and lighting/declutter use (OR = 1.87, 95% CI = 1.40-2.50) versus low HEM use. Recent falls were positively associated with overall HEM use (OR = 1.79, 95% CI = 1.72-1.87); high HEM use (OR = 2.89, 95% CI = 2.64-3.16), railings/grab bars use (OR = 2.32, 95% CI = 2.18-2.48), and lighting/declutter use (OR = 1.93, 95% CI = 1.79-2.08) were positively associated with recent falls. Modest associations were observed between HEM use and select (ie, atrial fibrillation, heart valve disease, stroke) cardiovascular outcomes. CONCLUSIONS: Among older women, disability-related conditions, including functional limitations and recent falls, were strongly associated with overall HEM use, high HEM use, and railings/grab bar use.

Weight Fluctuation and Cancer Risk in Postmenopausal Women: The Women's Health Initiative.

Background: Weight cycling, defined by an intentional weight loss and subsequent regain, commonly occurs in overweight and obese women and is associated with some negative health outcomes. We examined the role of various weight-change patterns during early to mid-adulthood and associated risk of highly prevalent, obesity-related cancers (breast, endometrial, and colorectal) in postmenopausal women.Methods: A total of 80,943 postmenopausal women (age, 63.4 ± 7.4 years) in the Women's Health Initiative Observational Study were categorized by self-reported weight change (weight stable; weight gain; lost weight; weight cycled [1-3, 4-6, 7-10, >10 times]) during early to mid-adulthood (18-50 years). Three site-specific associations were investigated using Cox proportional hazard models [age, race/ethnicity, income, education, smoking, alcohol, physical activity, hormone therapy, diet, and body mass index (BMI)].Results: A total of 7,464 (breast = 5,564; endometrial = 788; and colorectal = 1,290) incident cancer cases were identified between September 1994 and August 2014. Compared with weight stability, weight gain was significantly associated with risk of breast cancer [hazard ratio (HR), 1.11; 1.03-1.20] after adjustment for BMI. Similarly, weight cycling was significantly associated with risk of endometrial cancer (HR = 1.23; 1.01-1.49). Weight cycling "4 to 6 times" was most consistently associated with cancer risk, showing a 38% increased risk for endometrial cancer [95% confidence interval (CI), 1.08-1.76] compared with weight stable women.Conclusions: Weight gain and weight cycling were positively associated with risk of breast and endometrial cancer, respectively.Impact: These data suggest weight cycling and weight gain increase risk of prevalent cancers in postmenopausal women. Adopting ideal body-weight maintenance practices before and after weight loss should be encouraged to reduce risk of incident breast and endometrial cancers. Cancer Epidemiol Biomarkers Prev; 26(5); 779-86. ©2017 AACR.