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Endothelial and exercise vasodilation are reduced in postmenopausal females with obesity versus lean and overweight

Authors:
Stephen Fischer at The University of Texas Health Science Center at Houston
Stephen Fischer
Arun Maharaj
Arun Maharaj
Arun Maharaj
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Yejin Kang at University of British Columbia
Yejin Kang
Katherine Dillon at Texas Tech University
Katherine Dillon
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Background Obesity (OB) is highly prevalent in females after menopause, especially visceral adipose tissue (VAT) accumulation which contributes to endothelial dysfunction. The endothelium assists in regulating blood flow (BF) during exercise and is attenuated in females with OB. The purpose of this study was to examine upper and lower limb flow-mediated dilation (FMD) and BF regulation during graded low-intensity submaximal exercises in postmenopausal females with BMI in the lean (LN), overweight (OW) and OB categories. Methods Participants were grouped by body mass index (BMI) into LN (BMI 18.5–24.9 kg/m²; n = 11), OW (BMI 25.0–29.9 kg/m²; n = 15), and OB (BMI 30.0–39.9 kg/m²; n = 13). FMD of the brachial (BA-FMD) and superficial femoral arteries (FA-FMD) were assessed. Subsequently, BF and vascular conductance (VC) in the upper (BA-BF and BA-VC) and lower limbs (FA-BF and FA-VC) were measured during separate 3-stage incremental rhythmic handgrip and plantarflexion exercises. Results Significantly lower FA-FMD (P < 0.05) were seen in OB than LN and OW groups with no differences in BA-FMD. Increases in FA-BF and FA-VC were attenuated during the last stage of plantarflexion exercise at 30% of 1RM in OB (both P < 0.001) compared to LN and OW, while upper-body exercise vasodilation was unchanged. FA-BF and FA-VC during plantarflexion exercise were correlated to FA-FMD (FA-BF: r = 0.423, P = 0.007, FA-VC: r = 0.367, P = 0.021) and BMI (FA-BF: r = −0.386, P = 0.015, FA-VC: r = −0.456, P = 0.004). Conclusion Postmenopausal females with OB have reduced lower-limb endothelial and exercise vasodilator function during submaximal dynamic plantarflexion exercise compared to LN and OW. Our findings indicate that obesity may predict diminished leg endothelial function, BF and VC during exercise in postmenopausal females.
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ARTICLE
Clinical Research
Endothelial and exercise vasodilation are reduced in
postmenopausal females with obesity versus lean and
overweight
Stephen M. Fischer
1
, Arun Maharaj
1,2
, Yejin Kang
1
, Katherine N. Dillon
1
, Mauricio A. Martinez
1
and Arturo Figueroa
1
✉
© The Author(s), under exclusive licence to Springer Nature Limited 2024
BACKGROUND: Obesity (OB) is highly prevalent in females after menopause, especially visceral adipose tissue (VAT) accumulation
which contributes to endothelial dysfunction. The endothelium assists in regulating blood flow (BF) during exercise and is
attenuated in females with OB. The purpose of this study was to examine upper and lower limb flow-mediated dilation (FMD) and
BF regulation during graded low-intensity submaximal exercises in postmenopausal females with BMI in the lean (LN), overweight
(OW) and OB categories.
METHODS: Participants were grouped by body mass index (BMI) into LN (BMI 18.5–24.9 kg/m
2
;n=11), OW (BMI 25.0–29.9 kg/m
2
;
n=15), and OB (BMI 30.0–39.9 kg/m
2
;n=13). FMD of the brachial (BA-FMD) and superficial femoral arteries (FA-FMD) were
assessed. Subsequently, BF and vascular conductance (VC) in the upper (BA-BF and BA-VC) and lower limbs (FA-BF and FA-VC) were
measured during separate 3-stage incremental rhythmic handgrip and plantarflexion exercises.
RESULTS: Significantly lower FA-FMD (P< 0.05) were seen in OB than LN and OW groups with no differences in BA-FMD. Increases
in FA-BF and FA-VC were attenuated during the last stage of plantarflexion exercise at 30% of 1RM in OB (both P< 0.001) compared
to LN and OW, while upper-body exercise vasodilation was unchanged. FA-BF and FA-VC during plantarflexion exercise were
correlated to FA-FMD (FA-BF: r =0.423, P=0.007, FA-VC: r =0.367, P=0.021) and BMI (FA-BF: r =−0.386, P=0.015, FA-VC:
r=−0.456, P=0.004).
CONCLUSION: Postmenopausal females with OB have reduced lower-limb endothelial and exercise vasodilator function during
submaximal dynamic plantarflexion exercise compared to LN and OW. Our findings indicate that obesity may predict diminished
leg endothelial function, BF and VC during exercise in postmenopausal females.
International Journal of Obesity (2024) 48:1534–1541; https://doi.org/10.1038/s41366-024-01462-1
INTRODUCTION
Menopause is associated with fat mass gain, central redistribution
of body fat [1], and development of obesity [2]. A report from the
Framingham Heart Study states that middle-aged or older females
with obesity (OB) have a significantly higher relative risk of
cardiovascular disease (CVD) compared to those that are over-
weight (OW) [3]. A primary contributing factor to increased CVD
risk may be the presence of obesity-related endothelial dysfunc-
tion [4]. Particularly, accumulation of visceral adipose tissue (VAT)
seem to negatively affect endothelial function [5,6] and increases
CVD risk [7,8].
Flow-mediated dilation (FMD) of the upper (brachial) and lower
limb (femoral) conduit arteries are non-invasive measurements
used to estimate primarily nitric oxide-mediated endothelial
function [9,10]. Reduced brachial artery FMD (BA-FMD) is related
to increased CVD risk [11,12], and is significantly lower in young
and middle-aged females with OB compared to OW and lean (LN)
[13,14]. However, to date, superficial femoral artery FMD (FA-FMD)
has not been studied in the context of body mass index (BMI)
categories in postmenopausal females. Considering that FA-FMD
is not associated with BA-FMD [15], and that vascular aging may
be accelerated in the legs compared to the arms [16], it is
important to examine the extent to which obesity impairs
endothelial function and exercise blood flow (BF) of arms and
legs in females with different BMI categories.
During exercise, the endothelium partly accounts for BF regulation
in active skeletal muscles [17], as it is mostly mediated by metabolic
byproducts of muscle contractions like adenosine, adenosine tripho-
sphate, and lactic acid. This process occurs in order to counteract
increased sympathetic-mediated vasoconstriction, a phenomenon
commonly called “functional sympatholysis”[18]. Functional sym-
patholysis is attenuated with age in females [19]andmaybeachief
mediator of reduced exercise hyperemia [20]. Thus, increased muscle
sympathetic nerve activity (MSNA) during exercise after menopause
Received: 8 June 2023 Revised: 19 December 2023 Accepted: 2 January 2024
Published online: 17 January 2024
1
Department of Kinesiology and Sport Management, Texas Tech University, Lubbock, TX 79409, USA.
2
Department of Epidemiology and Cancer Control, St. Jude Children’s
Research Hospital, Memphis, TN 38105, USA. ✉email: arturo.figueroa@ttu.edu
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... The key findings from Fischer et al. [9] were that obesity was associated with vascular endothelial dysfunction in the lower, but not upper, limb. Similarly, obesity was associated with reduced blood flow and vascular conductance responses during plantar flexor, but not forearm, exercise. ...
... With these new results in mind [9], it remains unclear whether obesity would be associated with reduced upper limb vascular dysfunction later in life (e.g., 20 years after menopause). Additionally, research is warranted on the effects of HRT timing relative to the onset of menopause. ...
... For example, reduced physical activity with extended periods of sedentary behavior is correlated with lower vascular function [10]. Notably, the current study did show differences in physical activity between groups [9]. This led the authors to statistically control for physical activity when concluding on the group differences in vascular function, which is a strength of the present work. ...
View
... During handgrip exercise protocol, the ultrasound probe was placed on the upper arm, and the brachial artery diameter and mean blood velocity were continuously recorded at rest and during 3 min of exercise. Forearm muscle BF (FBF) and VC (FVC) were calculated as described in the previous study [34] and averaged by every 1 min for data analysis. Changes (∆) in FBF and FVC were calculated from rest (0 min) to the 1st, 2nd, and 3rd minute of exercise. ...
... During exercise, contracting muscles require greater BF and oxygen delivery to capillaries in order to meet an elevated metabolic demand [15,46], which primarily occurs via local vasodilation in limb arteries and arterioles [12,47]. However, arterial BF during exercise is blunted in older adults [34,48] due, in part, to reduced NO-mediated endothelial vasodilation [34,49,50]. In the current study, we found that 4 weeks of CIT (10 g/day) supplementation increased FBF and FVC during handgrip exercise by 47% and 49%, respectively, in hypertensive postmenopausal women. ...
... During exercise, contracting muscles require greater BF and oxygen delivery to capillaries in order to meet an elevated metabolic demand [15,46], which primarily occurs via local vasodilation in limb arteries and arterioles [12,47]. However, arterial BF during exercise is blunted in older adults [34,48] due, in part, to reduced NO-mediated endothelial vasodilation [34,49,50]. In the current study, we found that 4 weeks of CIT (10 g/day) supplementation increased FBF and FVC during handgrip exercise by 47% and 49%, respectively, in hypertensive postmenopausal women. ...
L-Citrulline Supplementation Improves Arterial Blood Flow and Muscle Oxygenation during Handgrip Exercise in Hypertensive Postmenopausal Women
Article
Full-text available
  • Jun 2024
Endothelial dysfunction decreases exercise limb blood flow (BF) and muscle oxygenation. Acute L-Citrulline supplementation (CIT) improves muscle tissue oxygen saturation index (TSI) and deoxygenated hemoglobin (HHb) during exercise. Although CIT improves endothelial function (flow-mediated dilation [FMD]) in hypertensive women, the impact of CIT on exercise BF and muscle oxygenation (TSI) and extraction (HHb) are unknown. We examined the effects of CIT (10 g/day) and a placebo for 4 weeks on blood pressure (BP), arterial vasodilation (FMD, BF, and vascular conductance [VC]), and forearm muscle oxygenation (TSI and HHb) at rest and during exercise in 22 hypertensive postmenopausal women. Compared to the placebo, CIT significantly (p < 0.05) increased FMD (Δ−0.7 ± 0.6% vs. Δ1.6 ± 0.7%) and reduced aortic systolic BP (Δ3 ± 5 vs. Δ−4 ± 6 mmHg) at rest and improved exercise BF (Δ17 ± 12 vs. Δ48 ± 16 mL/min), VC (Δ−21 ± 9 vs. Δ41 ± 14 mL/mmHg/min), TSI (Δ−0.84 ± 0.58% vs. Δ1.61 ± 0.46%), and HHb (Δ1.03 ± 0.69 vs. Δ−2.76 ± 0.77 μM). Exercise BF and VC were positively correlated with improved FMD and TSI during exercise (all p < 0.05). CIT improved exercise artery vasodilation and muscle oxygenation via increased endothelial function in hypertensive postmenopausal women.
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... Decreased estrogen and potentially higher levels of androgens leave the vascular endothelium susceptible to dysfunction. Additional risk factors that arise from being overweight are analogous to those seen in aging populations, and specifically in conduit artery sheer stress post-menopausal women [30] and decreased vasodilatory function induced by exercise and FMD in obese post-menopausal women [7]. ...
Limb-Specific Comparison of Flow-Mediated Dilation in Abdominal Obese Pre-menopausal Women
Article
Full-text available
  • Nov 2024
Purpose Normal aging can lead to arterial wall stiffening and development of atherosclerosis; however, the effects of overweight conditions can expedite the dysfunction of arterial health. In an earlier study, we identified in a group of abdominal obese pre-menopausal woman that during menses, these women had decreased vascular conductance of the brachial artery during dynamic hand-grip exercise. Endothelial function in abdominal obese (AO) premenopausal women could be associated with being highly sedentary which attenuates dilatory responses to FMD of both upper and lower limb vascular function. We hypothesized that the AO women would exhibit limb-specific differences in artery dilation with reduced dilation in the popliteal artery as compared to the brachial artery. Methods Artery dilatory responses in the brachial and popliteal arteries were assessed using flow-mediated dilation (FMD) in age-matched sedentary controls and AO groups during menses. Results Significant differences were found between groups including % BF, BMI, weight, waist to hip ratio, fasting blood glucose, and oxLDL. A between-group comparison revealed significantly lower percent dilation of the popliteal artery in AO participants compared to controls (p < 0.05) not present in the brachial arteries. Our results also indicate a difference in the time-to-peak (TP) of dilation between the control (33.38 ± 3.232) and AO (62.104 ± 5.813) groups ( p < 0.01). Following FMD correction with shear rate as the covariate, significant differences in FMD between the brachial and popliteal artery were abolished. Conclusion We conclude that young, AO women show a limb-specific difference in dilation of the upper and lower extremities when compared to controls. Thus, reductions in FMD of the popliteal artery could be due to impaired dilation of the downstream resistance vasculature preventing increases in shear within the leg conduit arteries not as significantly in the arms.
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Preserved ability to blunt sympathetically‐mediated vasoconstriction in exercising skeletal muscle of young obese humans
Article
Full-text available
  • Apr 2019
Sympathetic vasoconstriction is attenuated in exercising muscles to assist in matching of blood flow with metabolic demand. This “functional sympatholysis” may be impaired in young obese individuals due to greater sympathetic activation and/or reduced local vasodilatory capacity of both small and large arteries, but this remains poorly understood. We tested the hypothesis that functional sympatholysis is impaired in obese individuals compared with normal‐weight counterparts. In 36 obese and normal‐weight young healthy adults (n = 18/group), we measured forearm blood flow and calculated forearm vascular conductance (FVC) responses to reflex increases in sympathetic nerve activity induced by lower body negative pressure (LBNP) at rest and during rhythmic handgrip exercise at 15% and 30% of the maximal voluntary contraction (MVC). FVC was normalized to lean forearm mass. In normal‐weight individuals, LBNP evoked a decrease in FVC (−16.1 ± 5.7%) in the resting forearm, and the reduction in FVC (15%MVC: −8.1 ± 3.3%; 30%MVC: −1.0 ± 4.0%) was blunted during exercise in an intensity‐dependent manner (P < 0.05). Similarly, in obese individuals, LBNP evoked a comparable decrease in FVC (−10.9 ± 5.7%) in the resting forearm, with the reduction in FVC (15%MVC: −9.7 ± 3.3%; 30%MVC: −0.3 ± 4.0%) also blunted during exercise in an intensity‐dependent manner (P < 0.05). The magnitude of sympatholysis was similar between groups (P > 0.05) and was intensity‐dependent (P < 0.05). Our findings suggest that functional sympatholysis is not impaired in young obese individuals without overt cardiovascular diseases.
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Roles of Sedentary Behaviors and Unhealthy Foods in Increasing the Obesity Risk in Adult Men and Women: A Cross-Sectional National Study
Article
Full-text available
  • May 2018
Sedentary behaviors and dietary intake are independently associated with obesity risk. In the literature, only a few studies have investigated gender differences for such associations. The present study aims to assess the association of sedentary behaviors and unhealthy foods intake with obesity in men and women in a comparative manner. The analysis presented in this study was based on the data from a population-based, cross-sectional, nationally representative survey (Indonesian Basic Health Research 013/RISKESDAS 2013). In total, 222,650 men and 248,590 women aged 19–55 years were enrolled. A validated questionnaire, physical activity card, and food card were used for the assessments. The results showed that the prevalence of obesity (body mass index of ≥27.5 kg/m2 ) was higher in women (18.71%) than in men (8.67%). The mean body mass index in women tended to be higher than in men. After adjusting for age and education, the gender effect on obesity persisted in women and was more significant than in men. There was also a positive and significant effect on obesity of sedentary behaviors and unhealthy foods intake. Moreover, fatty and fried foods displayed a positive multiplicative interaction, increasing obesity risk in women more than in men and indicating a possible dietary risk in in women in relation to obesity. The study suggests that the implementation of educational programs on nutrition and physical activity is particularly important for promoting a healthy body weight among Indonesian women.
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The Impact of Obesity on the Regulation of Muscle Blood Flow during Exercise in Patients with Heart Failure with a Preserved Ejection Fraction
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  • Apr 2022
  • J Appl Physiol
Obesity is now considered a primary comorbidity in heart failure with preserved ejection fraction (HFpEF) pathophysiology, mediated largely by systemic inflammation. While there is accumulating evidence for a disease-related dysregulation of blood flow during exercise in this patient group, the role of obesity in the hemodynamic response to exercise remain largely unknown. Small muscle mass handgrip (HG) exercise was utilized to evaluate exercising muscle blood flow in non-obese (BMI < 30 kg/m ² , n=14) and obese (BMI > 30 kg/m ² ,n=40) patients with HFpEF. Heart rate (HR), stroke index (SI), cardiac index (CI), mean arterial pressure (MAP), forearm blood flow (FBF) and vascular conductance (FVC) were assessed during progressive intermittent HG exercise (15-30-45% maximal voluntary contraction, MVC). Blood biomarkers of inflammation (C-reactive protein (CRP) and Interleukin-6 (IL-6)) were also determined. Exercising FBF was reduced in obese patients with HFpEF at all work rates (15%: 304±42 vs. 229±15ml/min; 30%: 402±46 vs. 300±18ml/min; 45%: 484±55 vs. 380±23ml/min, non-obese vs. obese, p=0.025), and was negatively correlated with BMI (R=-.47, p<0.01). In contrast, no differences in central hemodynamics (HR, SI, CI, MAP) were found between groups. Proinflammatory biomarkers were markedly elevated in obese patients (CRP: 2133±418 vs. 4630±590ng/ml, p=0.02; IL-6: 2.9±0.3 vs. 5.2±0.7pg/ml, p = 0.04, non-obese vs. obese), and both biomarkers were positively correlated with BMI (CRP: R=0.40, p=0.03; IL-6: R=0.57, p<0.01). Together, these findings demonstrate the presence of obesity and an accompanying milieu of systemic inflammation as important factors in the dysregulation of exercising muscle blood flow in patients with HFpEF.
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Influence of Age and Estradiol on Sympathetic Nerve Activity Responses to Exercise in Women
Article
  • Oct 2021
Introduction: Postmenopausal women (PMW) display exaggerated increases in blood pressure during exercise, yet the mechanism(s) involved remain unclear. Moreover, research on the impact of menopausal changes in estradiol on cardiovascular control during exercise are limited. Methods: Herein, we tested the hypothesis that sympathetic responses during exercise are augmented in PMW compared to young women (YW), and estradiol administration attenuates these responses. Muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) were measured in 13 PMW (58 ± 1 yrs) and 17 YW (22 ± 1 yrs) during 2-min of isometric handgrip. Separately, MSNA and BP responses were measured during isometric handgrip in 6 PMW (53 ± 1 yrs) before and after 1 month of transdermal estradiol (100 μg/day). A period of post-exercise ischemia (PEI) to isolate muscle metaboreflex activation followed all handgrip bouts. Results: Resting MAP was similar between PMW and YW whereas MSNA was greater in PMW (23 ± 3 vs 8 ± 1 bursts/min; P < 0.05). During handgrip, the increases in MSNA (PMW Δ16 ± 2 vs YW Δ6 ± 1 bursts/min; P < 0.05) and MAP (PMW Δ18 ± 2 vs YW Δ12 ± 2 mmHg; P < 0.05) were greater in PMW and remained augmented during PEI. Estradiol administration decreased resting MAP but not MSNA in PMW. Moreover, MSNA (PMW (-E2) Δ27 ± 8 bursts/min vs. PMW (+E2) Δ12 ± 5 bursts/min; P < 0.05) and MAP (Δ31 ± 8 mmHg vs. Δ20 ± 6 mmHg; P < 0.05) responses during handgrip were attenuated in PMW following estradiol administration. Likewise, MAP responses during PEI were lower after estradiol. Conclusion: These data suggest that PMW exhibit an exaggerated MSNA and BP response to isometric exercise, due in part to heightened metaboreflex activation. Furthermore, estradiol administration attenuated BP and MSNA responses to exercise in PMW.
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Decline in endothelial function across the menopause transition in healthy women is related to decreased estradiol and increased oxidative stress
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  • Aug 2020
Endothelial function declines progressively across stages of the menopause transition; however, the mechanisms contributing to this decline are unknown. We hypothesized that differences in endothelial function among pre-, peri, and postmenopausal women are related to differences in estradiol and oxidative stress. Brachial artery flow-mediated dilation (FMD) was measured in 87 healthy women categorized by menopause stage (24 premenopausal, 17 early and 21 late perimenopausal, and 25 postmenopausal) before and after 3 days of ovarian hormone suppression (gonadotropin releasing hormone antagonist [GnRHant]) alone, and an additional 3 days of GnRHant with concurrent transdermal estradiol or placebo add-back treatment. In 82 women, FMD during acute vitamin C (antioxidant) infusion was measured before and after GnRHant + add-back. Before GnRHant, FMD was different among groups (p < 0.005; reduced across stages of menopause). Vitamin C increased FMD in late peri- and post- (p < 0.005) but not pre- or early perimenopausal women (p > 0.54). After GnRHant alone, FMD decreased in pre- and peri- (p < 0.01), but not postmenopausal women, and was restored to premenopausal levels by estradiol add-back in the pre- and perimenopausal groups. Vitamin C improved FMD in pre-, peri-, and postmenopausal women on GnRHant + placebo. There was no effect of vitamin C on FMD in women on GnRHant + estradiol. These observations support the concept that the decline in endothelial function across the menopause transition is related to the loss of ovarian estradiol. The decline in estradiol may alter redox balance, thereby increasing oxidative stress and impairing endothelial function.
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Sedentary Behavior and Cardiovascular Disease in Older Women: The OPACH Study
Article
  • Feb 2019
Background: Evidence that higher sedentary time is associated with higher risk for cardiovascular disease (CVD) is based mainly on self-reported measures. Few studies have examined whether patterns of sedentary time are associated with higher risk for CVD. Methods: Women from the Objective Physical Activity and Cardiovascular Health (OPACH) Study (n=5638, aged 63-97, mean age=79±7) with no history of myocardial infarction (MI) or stroke wore accelerometers for 4-to-7 days and were followed for up to 4.9 years for CVD events. Average daily sedentary time and mean sedentary bout duration were the exposures of interest. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CVD using models adjusted for covariates and subsequently adjusted for potential mediators (body mass index (BMI), diabetes, hypertension, and CVD-risk biomarkers [fasting glucose, high-density lipoprotein, triglycerides, and systolic blood pressure]). Restricted cubic spline regression characterized dose-response relationships. Results: There were 545 CVD events during 19,350 person-years. Adjusting for covariates, women in the highest (≥ ~11 hr/day) vs. the lowest (≤ ~9 hr/day) quartile of sedentary time had higher risk for CVD (HR=1.62; CI=1.21-2.17; p-trend <0.001). Further adjustment for potential mediators attenuated but did not eliminate significance of these associations (p-trend<.05, each). Longer vs. shorter mean bout duration was associated with higher risks for CVD (HR=1.54; CI=1.27-2.02; p-trend=0.003) after adjustment for covariates. Additional adjustment for CVD-risk biomarkers attenuated associations resulting in a quartile 4 vs. quartile 1 HR=1.36; CI=1.01-1.83; p-trend=0.10). Dose-response associations of sedentary time and bout duration with CVD were linear (P-nonlinear >0.05, each). Women jointly classified as having high sedentary time and long bout durations had significantly higher risk for CVD (HR=1.34; CI=1.08-1.65) than women with both low sedentary time and short bout duration. All analyses were repeated for incident coronary heart disease (MI or CVD death) and associations were similar with notably stronger hazard ratios. Conclusions: Both high sedentary time and long mean bout durations were associated in a dose-response manner with increased CVD risk in older women, suggesting that efforts to reduce CVD burden may benefit from addressing either or both component(s) of sedentary behavior.
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Follicle-stimulating hormone, but not cardiorespiratory fitness, is associated with flow-mediated dilation with advancing menopausal stage
Article
  • Nov 2018
  • MENOPAUSE
Objective: The aim of the study was to evaluate if there are differences in endothelial function before and after acute exercise in women at different menopausal stages with high and low cardiorespiratory fitness. Methods: Participants were healthy high-fit premenopausal (n = 11), perimenopausal (n = 12), and postmenopausal women (n = 13) and low-fit perimenopausal (n = 7) and postmenopausal women (n = 8). Brachial artery flow-mediated dilation (FMD) was measured before and after acute moderate intensity exercise. FMD was calculated as (Diameterpeak-Diameterbaseline)/ Diameterbaseline) × 100. Differences between high-fit women and between high- and low-fit perimenopausal and postmenopausal women were assessed with repeated-measure ANOVAs. Relations with FMD were assessed with Pearson correlations. Results: FMD was reduced with progressive menopausal stage in high-fit women (P = 0.005) and was lower in perimenopausal compared to postmenopausal women (P = 0.047). FMD was lower in high-fit compared to low-fit women (P = 0.006) and there was no relation between FMD and VO2peak (P > 0.05). There was an inverse relation between FMD and follicle-stimulating hormone (P < 0.05), but not estradiol (P > 0.05). Conclusions: These data suggest that endothelial function is lower with progressive menopausal stage in women with high cardiorespiratory fitness; that FMD is lower in women with higher cardiorespiratory fitness; and that FSH, but not estradiol, is associated with FMD.
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Cardiovascular Implications of the Menopause Transition: Endogenous Sex Hormones and Vasomotor Symptoms
Article
  • Dec 2018
  • OBSTET GYN CLIN N AM
The menopause transition (MT) is a critical period of women's lives marked by several physiologic changes and menopause-related symptoms that have implications for health. Risk for cardiovascular disease, the leading cause of death in women, increases after menopause, suggesting a contribution of the MT to its development. This article focuses on the relationship between 2 main features of the MT and women's cardiovascular health: (1) dynamic alterations of sex hormones, particularly endogenous estradiol and follicle-stimulating hormone, and (2) vasomotor symptoms, the cardinal symptom of the menopause. Limitations and future directions are discussed.
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Sympatholytic effect of intravascular ATP is independent of Nitric Oxide, prostaglandins, Na(+) /K(+) -ATPase, and KIR channels in humans
Article
Key points: Intravascular ATP attenuates sympathetic vasoconstriction (sympatholysis) similar to what is observed in contracting skeletal muscle of humans, and may be an important contributor to exercise hyperaemia. Similar to exercise, ATP-mediated vasodilatation occurs via activation of inwardly rectifying potassium channels (KIR ), and synthesis of nitric oxide (NO) and prostaglandins (PG). However, recent evidence suggests that these dilatatory pathways are not obligatory for sympatholysis during exercise; therefore, we tested the hypothesis that the ability of ATP to blunt α1 -adrenergic vasoconstriction in resting skeletal muscle would be independent of KIR , NO, PGs and Na+ /K+ -ATPase activity. Blockade of KIR channels alone or in combination with NO, PGs and Na+ /K+ -ATPase significantly reduced the vasodilatatory response to ATP, although intravascular ATP maintained the ability to attenuate α1 -adrenergic vasoconstriction. This study highlights similarities in the vascular response to ATP and exercise, and further supports a potential role of intravascular ATP in blood flow regulation during exercise in humans. Abstract: Exercise and intravascular ATP elicit vasodilatation that is dependent on activation of inwardly rectifying potassium (KIR ) channels, with a modest reliance on nitric oxide (NO) and prostaglandin (PG) synthesis. Both exercise and intravascular ATP attenuate sympathetic α-adrenergic vasoconstriction (sympatholysis). However, KIR channels, NO, PGs and Na+ /K+ -ATPase activity are not obligatory to observe sympatholysis during exercise. To further determine similarities between exercise and intravascular ATP, we tested the hypothesis that inhibition of KIR channels, NO and PG synthesis, and Na+ /K+ -ATPase would not alter the ability of ATP to blunt α1 -adrenergic vasoconstriction. In healthy subjects, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to intra-arterial infusion of phenylephrine (PE; α1 -agonist) during ATP or control vasodilatator infusion, before and after KIR channel inhibition alone (barium chloride; n = 7; Protocol 1); NO (l-NMMA) and PG (ketorolac) inhibition alone, or combined NO, PGs, Na+ /K+ -ATPase (ouabain) and KIR channel inhibition (n = 6; Protocol 2). ATP attenuated PE-mediated vasoconstriction relative to adenosine (ADO) and sodium nitroprusside (SNP) (PE-mediated ΔFVC: ATP: -16 ± 2; ADO: -38 ± 6; SNP: -59 ± 6%; P < 0.05 vs. ADO and SNP). Blockade of KIR channels alone or combined with NO, PGs and Na+ /K+ -ATPase, attenuated ATP-mediated vasodilatation (∼35 and ∼60% respectively; P < 0.05 vs. control). However, ATP maintained the ability to blunt PE-mediated vasoconstriction (PE-mediated ΔFVC: KIR blockade alone: -6 ± 5%; combined blockade:-4 ± 14%; P > 0.05 vs. control). These findings demonstrate that intravascular ATP modulates α1 -adrenergic vasoconstriction via pathways independent of KIR channels, NO, PGs and Na+ /K+ -ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis.
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Arterial ageing: From endothelial dysfunction to vascular calcification
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  • Mar 2017
  • J INTERN MED
Complex structural and functional changes occur in the arterial system with advancing age. The aged artery is characterized by changes in microRNA expression patterns, autophagy, smooth muscle cell migration and proliferation, and arterial calcification with progressively increased mechanical vessel rigidity and stiffness. With age the vascular smooth muscle cells modify their phenotype from contractile to ‘synthetic’ determining the development of intimal thickening as early as the second decade of life as an adaptive response to forces acting on the arterial wall. The increased permeability observed in intimal thickening could represent the substrate on which low-level atherosclerotic stimuli can promote the development of advanced atherosclerotic lesions. In elderly patients the atherosclerotic plaques tend to be larger with increased vascular stenosis. In these plaques there is a progressive accumulation of both lipids and collagen and a decrease of inflammation. Similarly the plaques from elderly patients show more calcification as compared with those from younger patients. The coronary artery calcium score is a well-established marker of adverse cardiovascular outcomes. The presence of diffuse calcification in a severely stenotic segment probably induces changes in mechanical properties and shear stress of the arterial wall favouring the rupture of a vulnerable lesion in a less stenotic adjacent segment. Oxidative stress and inflammation appear to be the two primary pathological mechanisms of ageing-related endothelial dysfunction even in the absence of clinical disease. Arterial ageing is no longer considered an inexorable process. Only a better understanding of the link between ageing and vascular dysfunction can lead to significant advances in both preventative and therapeutic treatments with the aim that in the future vascular ageing may be halted or even reversed.
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