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Postmenopausal women (PMW) display exaggerated increases in blood pressure (BP) 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. Herein, we tested the hypothesis that sympathetic responses during exercise are augmented in PMWcompared with 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 yr) and 17 YW (22 ± 1 yr) during 2 min of isometric handgrip. Separately, MSNA and BP responses were measured during isometric handgrip in six PMW (53 ± 1 yr) before and after 1 month of transdermal estradiol (100 μg·d-1). A period of postexercise ischemia (PEI) to isolate muscle metaboreflex activation followed all handgrip bouts.Resting MAP was similar between PMW and YW, whereas MSNA was greater in PMW (23 ± 3 vs 8 ± 1 bursts per minute; P0.05). During handgrip, the increases in MSNA (PMW Δ16 ± 2 vs YW Δ6 ± 1 bursts per minute; P0.05) and MAP (PMW Δ18 ± 2 vs YW Δ12 ± 2 mm Hg; P0.05) 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 per minute versus PMW (+E2) Δ12 ± 5 bursts per minute; P0.05) and MAP (Δ31 ± 8 mm Hg vs Δ20 ± 6 mm Hg; P0.05) responses during handgrip were attenuated in PMW after estradiol administration. Likewise, MAP responses during PEI were lower after estradiol.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.

Recent findings suggest that COVID-19 causes vascular dysfunction during the acute phase of the illness in otherwise healthy young adults. To date, to our knowledge, no studies have investigated the longer-term effects of COVID-19 on vascular function. Herein, we hypothesized that young, otherwise healthy adults who are past the acute phase of COVID-19 would exhibit blunted peripheral [brachial artery flow-mediated dilation (FMD) and reactive hyperemia] and cerebral vasodilator function (cerebral vasomotor reactivity to hypercapnia; CVMR) and increased central arterial stiffness. Sixteen young adults who were at least 4 wk past a COVID-19 diagnosis and 12 controls who never had COVID-19 were studied. Eight subjects with COVID-19 were symptomatic (SYM) and eight were asymptomatic (ASYM) at the time of testing. FMD and reactive hyperemia were not different between COVID and control groups. However, FMD was lower in SYM (3.8 ± 0.6%) compared with ASYM (6.8 ± 0.9%; P = 0.007) and control (6.8 ± 0.6%; P = 0.003) with no difference between ASYM and control. Similarly, peak blood velocity following cuff release was lower in SYM (47 ± 8 cm/s) compared with ASYM (64 ± 19 cm/s; P = 0.025) and control (61 ± 14 cm/s; P = 0.036). CVMR and arterial stiffness were not different between any groups. In summary, peripheral macrovascular and microvascular function, but not cerebral vascular function or central arterial stiffness were blunted in young adults symptomatic beyond the acute phase of COVID-19. In contrast, those who were asymptomatic had similar vascular function compared with controls who never had COVID-19. NEW & NOTEWORTHY This study was the first to investigate the persistent effects of COVID-19 on vascular function in otherwise healthy young adults. We demonstrated that peripheral macrovascular and microvascular vasodilation was significantly blunted in young adults still symptomatic from COVID-19 beyond the acute phase (>4 wk from diagnosis), whereas those who become asymptomatic have similar vascular function compared with controls who never had COVID-19. In contrast, cerebral vascular function and central arterial stiffness were unaffected irrespective of COVID-19 symptomology.

Ever since their origin more than one half-century ago, microneurographic recordings of sympathetic nerve activity have significantly advanced our understanding of the generation and regulation of central sympathetic outflow in human health and disease. For example, it is now appreciated that a myriad of disease states exhibit chronic sympathetic overactivity, a significant predictor of cardiovascular morbidity and mortality. Although microneurographic recordings allow for the direct quantification of sympathetic outflow, they alone do not provide information with respect to the ensuing sympathetically mediated vasoconstriction and blood pressure (BP) response. Therefore, the study of vascular and/or BP responses to sympathetic outflow (i.e., sympathetic transduction) has now emerged as an area of growing interest within the field of neural cardiovascular control in human health and disease. To date, studies have primarily examined sympathetic transduction under two distinct paradigms: when reflexively evoking sympatho-excitation through the induction of a laboratory stressor (i.e., sympathetic transduction during stress) and/or following spontaneous bursts of sympathetic outflow occurring under resting conditions (i.e., sympathetic transduction at rest). The purpose of this brief review is to highlight how our physiological understanding of sympathetic transduction has been advanced by these studies and to evaluate the primary analytical techniques developed to study sympathetic transduction in humans. We also discuss the framework by which the assessment of sympathetic transduction during stress reflects a fundamentally different process relative to sympathetic transduction at rest and why findings from investigations using these different techniques should be interpreted as such and not necessarily be considered one and the same.

The use of spontaneous bursts of muscle sympathetic nerve activity (MSNA) to assess arterial baroreflex control of sympathetic nerve activity has seen increased utility in studies of both health and disease. However, methods used for analyzing spontaneous MSNA baroreflex sensitivity are highly variable across published studies. Therefore, we sought to comprehensively examine methods of producing linear regression slopes to quantify spontaneous MSNA baroreflex sensitivity in a large cohort of subjects ( n = 150) to support a standardized procedure for analysis that would allow for consistent and comparable results across laboratories. The primary results demonstrated that 1) consistency of linear regression slopes was considerably improved when the correlation coefficient was above −0.70, which is more stringent compared with commonly reported criterion of −0.50, 2) longer recording durations increased the percentage of linear regressions producing correlation coefficients above −0.70 (1 min = 15%, 2 min = 28%, 5 min = 53%, 10 min = 67%, P < 0.001) and reaching statistical significance (1 min = 40%, 2 min = 69%, 5 min = 78%, 10 min = 89%, P < 0.001), 3) correlation coefficients were improved with 3-mmHg versus 1-mmHg and 2-mmHg diastolic blood pressure (BP) bin size, and 4) linear regression slopes were reduced when the acquired BP signal was not properly aligned with the cardiac cycle triggering the burst of MSNA. In summary, these results support the use of baseline recording durations of 10 min, a correlation coefficient above −0.70 for reliable linear regressions, 3-mmHg bin size, and importance of properly time-aligning MSNA and diastolic BP. Together, these findings provide best practices for determining spontaneous MSNA baroreflex sensitivity under resting conditions for improved rigor and reproducibility of results.

INTRODUCTION Adults with obesity are at an increased risk of incident hypertension. Regular aerobic exercise is recommended for the prevention and treatment of hypertension, but whether young adults with obesity exhibit impaired postexercise blood pressure (BP) and vascular responses remains unclear. PURPOSE We tested the hypothesis that young adults with obesity exhibit attenuated postexercise hypotension (PEH) and postexercise peripheral vasodilation compared with young adults without obesity. METHODS Thirty-six normotensive adults without and with obesity (11 men and 7 women per group) underwent measurements of brachial and central BP, and leg blood flow (Doppler ultrasound) at baseline and at 30, 60, and 90 min after acute 1-h moderate-intensity cycling. Leg vascular conductance (LVC) was calculated as flow/mean arterial pressure. RESULTS Both groups exhibited similar brachial and central PEH (peak change from baseline, -2 and -4 mm Hg for brachial and central systolic BPs, respectively, for both groups; time effect, P < 0.05). Both groups also exhibited postexercise peripheral vasodilation, assessed via LVC (time effect, P < 0.05), but its overall magnitude was smaller in young adults with obesity (LVC change from baseline, +47% ± 37%, +29% ± 36%, and +20% ± 29%) compared with young adults without obesity (LVC change from baseline, +88% ± 58%, +59% ± 54%, and +42% ± 51%; group effect, P < 0.05). CONCLUSIONS Although obesity did not impair PEH after acute moderate-intensity exercise, young adults with obesity exhibited smaller postexercise peripheral vasodilation compared with young adults without obesity. Collectively, these findings have identified evidence for obesity-induced alterations in the peripheral vasculature after exercise.

Cardiovascular disease (CVD) affects individuals of all races and ethnicities; however, its prevalence is highest in non-Hispanic black individuals (BL) relative to other populations. While previous research has provided valuable insight into elevated CVD risk in the BL population, this work has been almost exclusively conducted in men. This is alarming given that BL women suffer from CVD at an equivalent rate to BL men and each has a greater prevalence when compared to all other ethnicities, regardless of sex. The importance of investigating sex differences in mechanisms of cardiovascular function is highlighted by the National Institute of Health requiring sex to be considered as a biological variable in research studies to better our "understanding of key sex influences on health processes and outcomes." The mechanism(s) responsible for the elevated CVD risk in BL women remains unclear and is likely multifactorial. Limited studies in BL women suggest that, while impaired vasodilator capacity is involved, heightened vasoconstrictor tone and/or responsiveness may also contribute. Within this mini-review, we will discuss potential mechanisms of elevated rates of hypertension and other CVDs in BL individuals with a particular focus on young, otherwise healthy, college-aged women. To stimulate academic thought and future research, we will also discuss potential mechanisms for impaired vascular function in BL women, as well as possible divergent mechanisms between BL men and women based on either preliminary data or plausible speculation extending from findings in the existing literature. Last, we will conclude with potential future research directions aimed at better understanding the elevated risk for hypertension and CVD in BL women.

NEW FINDINGS What is the central question of this study? The prevalence of hypertension in black individuals exceeds that in other racial groups. Despite this well-known heightened risk, the underlying contributory factors remain incompletely understood. We hypothesized that young black men would exhibit augmented beat-to-beat blood pressure variability compared with white men and that black men would exhibit augmented total peripheral resistance variability. What is the main finding and its importance? We demonstrate that young, healthy black men exhibit greater resting beat-to-beat blood pressure variability compared with their white counterparts, which is accompanied by greater variability in total peripheral resistance. These swings in blood pressure over time might contribute to the enhanced cardiovascular risk profile in black individuals. ABSTRACT The prevalence of hypertension in black (BL) individuals exceeds that in other racial groups. Recently, resting beat-to-beat blood pressure (BP) variability has been shown to predict cardiovascular risk and detect target organ damage better than ambulatory BP monitoring. Given the heightened risk in BL individuals, we hypothesized young BL men would exhibit augmented beat-to-beat BP variability compared with white (WH) men. Furthermore, given studies reporting reduced vasodilatation and augmented vasoconstriction in BL individuals, we hypothesized that BL men would exhibit augmented variability in total peripheral resistance (TPR). In 45 normotensive men (24 BL), beat-to-beat BP (Finometer) was measured during 10-20 min of quiet rest. Cardiac output and TPR were estimated (Modelflow method). Despite similar resting BP, BL men exhibited greater BP standard deviation (e.g. systolic BP SD; BL, 7.1 ± 2.2 mmHg; WH, 5.4 ± 1.5 mmHg; P = 0.006) compared with WH men, which was accompanied by a greater TPR SD (P = 0.003), but not cardiac output SD (P = 0.390). Other traditional measures of variability provided similar results. Histogram analysis indicated that BL men exhibited a greater percentage of cardiac cycles with BPs higher (> +10 mmHg higher) and lower (< -8 mmHg lower) than mean systolic BP compared with WH men (interaction, P

Despite the adverse effects of substance use on health among individuals with preexisting cardiovascular disease (CVD), little is known about trends and correlates for substance use among individuals with CVD. We examined trends of use in tobacco, alcohol, and cannabis among US adults with heart disease. Using nationally representative data from the 2015–2019 National Survey on Drug Use and Health (N = 7339), we conducted survey-adjusted logistic regression analyses to test the significance of trends in substance use while controlling for sociodemographic factors and related correlates. Results showed that the prevalence of cannabis use among adults with a heart condition significantly increased. Notably, the prevalence of cannabis use increased by 91% among non-Hispanic Whites, while the increasing trends were not present among other racial/ethnic groups. Our results also showed that increase in cannabis use was associated with easier access, lower disapproval, and risk perceptions of cannabis. Special attention is needed to raise awareness of the risk associated with cannabis use among individuals with CVD and the implementation of an early screening and treatment strategy among those with CVD.

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide considered to be causally implicated in hypertension and the development of cardiovascular disease. Increased ET-1 is commonly associated with reduced NO bioavailability and impaired vascular function; however, whether chronic elevation of ET-1 directly impairs endothelium-dependent relaxation (EDR) remains elusive. Herein, we report that (1) prolonged ET-1 exposure (ie, 48 hours) of naive mouse aortas or cultured endothelial cells did not impair EDR or reduce eNOS (endothelial NO synthase) activity, respectively (P>0.05); (2) mice with endothelial cell–specific ET-1 overexpression did not exhibit impaired EDR or reduced eNOS activity (P>0.05); (3) chronic (8 weeks) pharmacological blockade of ET-1 receptors in obese/hyperlipidemic mice did not improve aortic EDR or increase eNOS activity (P>0.05); and (4) vascular and plasma ET-1 did not inversely correlate with EDR in resistance arteries isolated from human subjects with a wide range of ET-1 levels (r=0.0037 and r=−0.1258, respectively). Furthermore, we report that prolonged ET-1 exposure downregulated vascular UCP-1 (uncoupling protein-1;P

Cardiovascular disease (CVD) accounts for a third of all deaths in the United States making it the leading cause of morbidity and mortality. Although CVD affects individuals of all races/ethnicities, the prevalence of CVD is highest in non-Hispanic black (BL) individuals relative to other populations. The mechanism(s) responsible for elevated CVD risk in the BL population remains incompletely understood. However, impaired vascular vasodilator capacity and exaggerated vascular vasoconstrictor responsiveness are likely contributing factors, both of which are present even in young, otherwise healthy BL individuals. Within this review, we highlight some historical and recent data, collected from our laboratories, of impaired vascular function, in terms of reduced vasodilator capacity and heightened vasoconstrictor responsiveness, in the peripheral and cerebral circulations in BL individuals. We provide data that such impairments may be related to elevated oxidative stress and subsequent reduction in nitric oxide bioavailability. In addition, divergent mechanisms of impaired vasodilatory capacity between BL men and women are discussed. Finally, we propose several directions where future research is needed to fill in knowledge gaps, which will allow for better understanding of the mechanisms contributing to impaired vascular function in this population. Ultimately, this information will allow for better lifestyle and therapeutic approaches to be implemented in an effort to minimize the increased CVD burden in the BL population.

Increased consumption of inorganic phosphate (Pi), an abundant ingredient in processed foods, has been associated with elevated cardiovascular disease risk; however, studies investigating underlying mechanisms are limited. Recently, high dietary Pi was shown to exaggerate the pressor response to static muscle contraction in rodents in part because of overactivation of metabolically sensitive skeletal muscle afferents. Whether acute high Pi consumption affects muscle metaboreflex activation in humans remains unknown. Furthermore, although acute high Pi consumption has been shown to impair vascular function in young healthy men, equivocal results have been reported. Therefore, we hypothesized that acute high Pi consumption augments mean arterial pressure (MAP) responses during muscle metaboreflex activation, impairs endothelial function, and increases arterial stiffness in young healthy men. Subjects performed 35% maximal voluntary contraction static handgrip (HG), followed by postexercise ischemia (PEI) to isolate muscle metaboreflex activation. Resting flow-mediated dilation (FMD) and arterial stiffness were assessed. Measures were made before (pre) and 60 min after (post) subjects consumed either a high-phosphate drink (2,000 mg phosphorus and 1,520 mg sodium) or a sodium drink (1,520 mg sodium; control). MAP responses during HG (preΔ = +23 ± 3 mmHg; postΔ = +21 ± 2 mmHg; P = 0.101) and PEI (preΔ = +21 ± 4 mmHg; postΔ = +18 ± 3 mmHg; P = 0.184) were similar before and after Pi consumption. In contrast, FMD was significantly attenuated following Pi (pre = 5.1 ± 0.5%; post = 3.5 ± 0.5%; P = 0.010), whereas arterial stiffness remained unchanged. There were no changes in any measured variable after control drink consumption. In summary, although the muscle metaboreflex remains unaffected following acute high Pi consumption in young healthy men, endothelial function is impaired. NEW & NOTEWORTHY This study was the first to investigate the influence of acute high-phosphate consumption on the pressor response during isometric handgrip and isolated muscle metaboreflex activation during postexercise ischemia in young healthy humans. We demonstrated that a single high dose of phosphate (2,000 mg) did not augment blood pressure in response to exercise or isolated muscle metaboreflex activation, but endothelial function was blunted in young healthy men.

Approximately 60% of patients with type 2 diabetes mellitus (T2D) develop hypertension. Recent work also indicates greater blood pressure (BP) excursions throughout the day in T2D. Collectively, these findings suggest altered BP control in T2D. Although muscle sympathetic nerve activity (MSNA) recordings in T2D have provided equivocal results, quantification of MSNA alone does not account for ensuing vasoconstriction and BP responses elicited by MSNA. Thus, we tested the hypothesis that patients with T2D exhibit enhanced sympathetic transduction to BP. MSNA (microneurography) and beat-to-beat BP (Finometer) were measured at rest in 21 T2D and 13 age-matched and body mass index–matched control subjects and, signal-averaging was performed to quantify the mean arterial pressure and total vascular conductance responses to spontaneous bursts of MSNA. The peak mean arterial pressure and total vascular conductance responses to spontaneous MSNA were similar between T2D and control (both P >0.05). However, further analysis, separating T2D into those taking statins (n=13, T2D +statin) and not taking statins (n=8, T2D −statin), indicated that T2D −statin patients (4.2±0.6 mm Hg) exhibited greater peak mean arterial pressure responses compared with both T2D +statin patients (2.5±0.3 mm Hg, P =0.01) and control (control: 2.8±0.3 mm Hg, P =0.02). Likewise, nadir total vascular conductance responses to spontaneous MSNA bursts were greater in T2D −statin patients (T2D −statin: −3.3±0.6 mL/(min·mm Hg), T2D +statin: −1.6±0.3 mL/(min·mm Hg), P =0.03; control −2.2±0.3 mL/(min·mm Hg), P =0.08). Notably, T2D +statin patients exhibited similar peak mean arterial pressure and total vascular conductance responses to MSNA compared with control. Collectively, these findings demonstrate, for the first time, that patients with T2D exhibit augmented sympathetic transduction and this effect seems to be offset by statin therapy.

Muscle sympathetic nerve activity (MSNA) influences the mechanical properties (ie, vascular smooth muscle tone and stiffness) of peripheral arteries, but it remains controversial whether MSNA contributes to stiffness of central arteries, such as the aorta and carotids. We examined whether elevated MSNA (age-related) would be independently associated with greater stiffness of central (carotid-femoral pulse wave velocity [PWV]) and peripheral (carotid-brachial PWV) arteries, in addition to lower carotid compliance coefficient, in healthy men and women (n=88, age: 19–73 years, 52% men). We also examined whether acute elevations in MSNA without increases in mean arterial pressure using graded levels of lower body negative pressure would augment central and peripheral artery stiffness in young (n=15, 60% men) and middle-age/older (MA/O, n=14, 43% men) adults. Resting MSNA burst frequency (bursts·min −1 ) was significantly correlated with carotid-femoral PWV ( R =0.44, P R =0.32, P =0.004), and carotid compliance coefficient ( R =0.28, P =0.01) after controlling for sex, mean arterial pressure, heart rate, and waist-to-hip ratio (central obesity), but these correlations were abolished after further controlling for age (all P >0.05). In young and MA/O adults, MSNA was elevated during lower body negative pressure ( P −1 , P =0.53) and carotid-brachial PWV (young: Δ+0.7±0.3 versus MA/O: Δ+0.7±0.5 m·s −1 , P =0.92), whereas carotid compliance coefficient during lower body negative pressure was significantly reduced in young but not MA/O (young: Δ−0.04±0.01 versus MA/O: Δ0.001±0.008 mm 2 ·mm Hg −1 , P

The arterial baroreflex (ABR) resets during exercise in an intensity-dependent manner to operate around a higher blood pressure with maintained sensitivity. This review provides a historical perspective of ABR resetting and the involvement of other neural reflexes in mediating exercise resetting. Furthermore, we discuss potential underlying signaling mechanisms that may contribute to exercise ABR resetting in physiological and pathophysiological conditions.

Emerging evidence suggests that type 2 diabetes (T2D) may impair the ability to properly adjust the circulation during exercise with augmented blood pressure (BP) and an attenuated contracting skeletal muscle blood flow (BF) response being reported. This review provides a brief overview of the current understanding of these altered exercise responses in T2D and the potential underlying mechanisms, with an emphasis on the sympathetic nervous system and its regulation during exercise. The research presented support augmented sympathetic activation, heightened BP, reduced skeletal muscle BF, and impairment in the ability to attenuate sympathetically mediated vasoconstriction (i.e., functional sympatholysis) as potential drivers of neurovascular dysregulation during exercise in T2D. Furthermore, emerging evidence supporting a contribution of the exercise pressor reflex and central command is discussed along with proposed future directions for studies in this important area of research.

PURPOSE Non-Hispanic Black individuals have a blunted ability to vasodilate at rest compared with other racial groups. Limited studies have investigated blood flow responses to exercise in Black individuals. Recently, our laboratory demonstrated that Black men exhibit attenuated increases in forearm vascular conductance (FVC) during steady-state rhythmic handgrip. The mechanisms for this remain unknown. Herein, we used single muscle contractions, a modality that allows for assessment of rapid-onset vasodilation (ROV) independent of major elevations in shear stress, tissue metabolism, and systemic hemodynamics. METHODS Ten young, healthy Black and White men performed single forearm contractions at 20%, 40%, and 60% maximal voluntary contraction (MVC). In addition, cuff inflations were performed on the forearm to examine the contribution of mechanical compression to ROV. Forearm blood flow (FBF; duplex Doppler ultrasound), heart rate (ECG), and mean arterial pressure (Finometer) were continuously measured. FVC was calculated as FBF/mean arterial pressure. RESULTS Baseline FVC (White men vs Black men, 0.75 ± 0.11 vs 0.80 ± 0.09 mL·min-1·mm Hg-1; P = 0.73), FBF, and MVCs (White men vs Black men, 54 ± 2 vs 54 ± 2 kg; P = 0.95) were similar between the groups. After single contractions, both groups exhibited intensity-dependent FVC and FBF increases during ROV; however, these responses were attenuated in the Black group at all intensities (e.g., 60%MVC FVC: White men vs Black men, +371% ± 37% vs +220% ± 23% baseline; P = 0.001). FVC and FBF responses to cuff inflation alone were also attenuated in Black individuals (P < 0.001). CONCLUSIONS Collectively, these data indicate that Black men have an overall blunted ability to rapidly vasodilate compared with young White men.

Background: Augmented skeletal muscle metaboreflex activation may accompany chronic obstructive pulmonary disease (COPD). The maintained metaboreflex control of mean arterial pressure (MAP) that has been reported may reflect limited evaluation using only one moderate bout of static handgrip (HG) and following postexercise ischaemia (PEI). Objective: We tested the hypothesis that cardiovascular and respiratory responses to high-intensity static HG and isolated metaboreflex activation during PEI are augmented in COPD patients. Methods: Ten patients with moderate to severe COPD and eight healthy age- and BMI-matched controls performed two-minute static HG at moderate (30% maximal voluntary contraction; MVC) and high (40% MVC) intensity followed by PEI. Results: Despite similar ratings of perceived exertion, arm muscle mass and strength, COPD patients demonstrated lower MAP responses during both HG intensities compared with controls (time × group interaction, p .05). We found no between-group differences in heart rate, respiratory rate, or estimated minute ventilation during HG or PEI. Conclusion: These results suggest that the pressor response to high-intensity HG is blunted in COPD patients. Moreover, despite inducing a strong cardiovascular and respiratory stimulus, skeletal muscle metaboreflex activation evoked similar responses in COPD patients and controls.

The magnitude of blood pressure (BP) and muscle sympathetic nerve activity (MSNA) responses to laboratory stressors is commonly used to compare neurocardiovascular responsiveness between groups and conditions. However, no studies have rigorously examined the reproducibility of BP and MSNA responsiveness. Here, we assess the within-visit reproducibility of BP (finger photoplethysmography) and MSNA (microneurography) responses to isometric handgrip (HG) and postexercise ischemia (PEI) in young healthy adults (n = 30). In a subset (n = 21), we also examined the between-visit reproducibility of responsiveness to HG, PEI, and the cold pressor test (CPT). Intraclass correlation coefficients (ICCs) were used as a primary reproducibility measure (e.g., ICC >0.75 is considered very good). Within a visit, the increase in mean arterial pressure during HG [ICC = 0.85 (0.69–0.93); P < 0.001] and PEI [ICC = 0.85 (0.69–0.93); P < 0.001] demonstrated very good reproducibility. Furthermore, the between-visit reproducibility of the pressor response to HG [ICC = 0.85 (0.62–0.94); P < 0.001], PEI [ICC = 0.84 (CI = 0.58–0.94); P < 0.001], and the CPT [ICC = 0.89 (0.72–0.95) P < 0.001]) were also very good. However, there was greater variability in both the within- [HG: ICC = 0.58 (−0.22–0.85), P = 0.001; PEI: ICC = 0.33 (−0.24–0.69), P = 0.042] and between-visit reproducibility of MSNA responsiveness [HG: ICC = 0.87 (0.53–0.96), P = 0.001; PEI: ICC = 0.24 (−0.62–0.78), P = 0.27; CPT: ICC = 0.77 (0.29–0.93), P = 0.007]. The magnitude of the BP response to several standard laboratory stimuli was very good, whereas the variability of the MSNA response to these perturbations was generally less consistent, particularly during PEI. These data provide novel insight for both study design and data interpretation when comparing neurocardiovascular responsiveness between different conditions, groups, or studies, as well as before and after interventions/treatments. NEW & NOTEWORTHY The magnitude of the increases in blood pressure and muscle sympathetic nerve activity in response to sympathoexcitatory stimuli such as static handgrip, postexercise ischemia, and the cold pressor test are commonly used to assess neurocardiovascular responsiveness. However, limited studies have comprehensively examined the reproducibility of these responses. We demonstrate that the reproducibility of the pressor response to these perturbations was very good within an individual, whereas the reproducibility of the MSNA response was less consistent.

Black men have attenuated increases in forearm vascular conductance (FVC) and forearm blood flow (FBF) during moderate- and high-intensity rhythmic handgrip exercise compared with White men, but the underlying mechanisms are unclear. Here, we tested for the first time the hypothesis that functional sympatholysis (i.e., attenuation of sympathetic vasoconstriction in the exercising muscles) is impaired in Black men compared with White men. Thirteen White and 14 Black healthy young men were studied. FBF (duplex Doppler ultrasound) and mean arterial pressure (MAP; Finometer) were measured at rest and during rhythmic handgrip exercise at 30% maximal voluntary contraction. FVC was calculated as FBF/MAP. Sympathetic activation was induced via lower body negative pressure (LBNP) at −20 Torr for 2 min at rest and from the 3rd to the 5th min of handgrip. Sympathetic vasoconstriction was assessed as percent reductions in FVC during LBNP. The groups presented similar resting FVC, FBF, and MAP. During LBNP at rest, reductions in FVC were not different between White (−35 ± 10%) and Black men (−32 ± 14%, P = 0.616), indicating similar reflex-induced sympathetic vasoconstriction. During handgrip exercise, there were minimal reductions in FVC with LBNP in either group (White: −1 ± 7%; Black: +1 ± 8%; P = 0.523), indicating functional sympatholysis in both groups. Thus, contrary to our hypothesis, our findings indicate a preserved functional sympatholysis in healthy young Black men compared with White men, suggesting that this mechanism does not appear to contribute to reduced exercise hyperemia during moderate-intensity rhythmic handgrip in this population.

Twenty-three young adults (4 Females, 25.13 ± 3.72 years) performed an intermittent maximal handgrip force task using their dominant hand for 20 min (3.5 s squeeze/6.5 s release, 120 blocks) with concurrent cortical activity imaging by functional Near-Infrared Spectroscopy (fNRIS; OMM-3000, Shimadzu Corp., 111 channels). Subjects were grouped as physically active (n = 10) or inactive (n = 12) based on a questionnaire (active-exercise at least four times a week, inactive- exercise less than two times a week). We explored how motor task fatigue affected the vasomotion-induced oscillations in ΔHbO as measured by fNIRS at each hemodynamic frequency band: endothelial component (0.003–0.02 Hz) associated to microvascular activity, neurogenic component (0.02–0.04 Hz) related to intrinsic neuronal activity, and myogenic component (0.04–0.15 Hz) linked to activity of smooth muscles of arterioles. To help understand how these three neurovascular regulatory mechanisms relate to handgrip task performance we quantified several dynamic fNIRS metrics, including directional phase transfer entropy (dPTE), a computationally efficient and data-driven method used as a marker of information flow between cortical regions, and directional connectivity (DC), a means to compute directionality of information flow between two cortical regions. The relationship between static functional connectivity (SFC) and functional connectivity variability (FCV) was also explored to understand their mutual dependence for each frequency band in the context of handgrip performance as fatigued increased. Our findings ultimately showed differences between subject groups across all fNIRS metrics and hemodynamic frequency bands. These findings imply that physical activity modulates neurovascular control mechanisms at the endogenic, neurogenic, and myogenic frequency bands resulting in delayed fatigue onset and enhanced performance. The dynamic cortical network metrics quantified in this work for young, healthy subjects provides baseline measurements to guide future work on older individuals and persons with impaired cardiovascular health.

The black population exhibits attenuated vasodilatory function across their lifespan, yet little is known regarding the mechanisms of this impairment. Recent evidence suggests a potential role for oxidative stress. Therefore, we tested the hypothesis that NADPH oxidase (NOX) and/or xanthine oxidase (XO) contribute to blunted nitric oxide (NO)-mediated cutaneous microvascular function in young black adults. In 30 white and black subjects (8 men and 7 women in each group), local heating was performed while NOX and XO were inhibited by apocynin and allopurinol, respectively, via intradermal microdialysis. The plateau in cutaneous vascular conductance (red blood cell flux/mean arterial pressure) during 39°C local heating at each site was compared with a control site perfused with lactated Ringer solution. Subsequent inhibition of NO synthase via Nω-nitro-l-arginine methyl ester allowed for quantification of the NO contribution to vasodilation during heating. Black individuals, relative to white individuals, had a blunted cutaneous vascular conductance plateau at the control site (45 ± 9 vs. 68 ± 13%max, P < 0.001) that was increased by both apocynin (61 ± 15%max, P < 0.001) and allopurinol (58 ± 17%max, P = 0.005). Black men and black women had similar responses to heating at the control site ( P = 0.99), yet apocynin and allopurinol increased this response only in black men (both P < 0.001 vs. control). The NO contribution was also increased via apocynin and allopurinol exclusively in black men. These findings suggest that cutaneous microvascular function is reduced because of NOX and XO activity in black men but not black women, identifying a novel sex difference in the mechanisms that contribute to blunted vascular responses in the black population. NEW & NOTEWORTHY We demonstrate that cutaneous microvascular responses to local heating are consistently reduced in otherwise healthy young black men and women relative to their white counterparts. Inhibition of NADPH oxidase and xanthine oxidase via apocynin and allopurinol, respectively, augments microvascular function in black men but not black women. These data reveal clear sex differences in the mechanisms underlying the racial disparity in cutaneous microvascular function.

The introduction of duplex Doppler ultrasound almost half a century ago signified a revolutionary advance in the ability to assess limb blood flow in humans. It is now widely used to assess blood flow under a variety of experimental conditions to study skeletal muscle resistance vessel function. Despite its pervasive adoption, there is substantial variability between studies in relation to experimental protocols, procedures for data analysis, and interpretation of findings. This guideline results from a collegial discussion among physiologists and pharmacologists, with the goal of providing general as well as specific recommendations regarding the conduct of human studies involving Doppler ultrasound-based measures of resistance vessel function in skeletal muscle. Indeed, the focus is on methods used to assess resistance vessel function and not upstream conduit artery function (i.e., macrovasculature), which has been expertly reviewed elsewhere. In particular, we address topics related to experimental design, data collection, and signal processing as well as review common procedures used to assess resistance vessel function, including postocclusive reactive hyperemia, passive limb movement, acute single limb exercise, and pharmacological interventions. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-doppler-ultrasound-and-resistance-vessel-function/ .

NEW FINDINGS What is the central question of this study? Water drinking increases muscle sympathetic nerve activity (MSNA), and it increases arterial blood pressure (ABP) in older populations but not in young healthy subjects. Does an increase in gain of arterial baroreflex control of MSNA contribute to maintenance of ABP after water drinking in healthy young subjects? What is the main finding and its importance? The gain of arterial baroreflex control of MSNA was increased and remained elevated 60 min after water drinking (500 ml) but remained unchanged after saline intake. An enhancement in gain of arterial baroreflex control of MSNA contributes to the maintenance of ABP after water drinking in young healthy subjects, probably via osmosensitive mechanisms. ABSTRACT Water drinking increases muscle sympathetic nerve activity (MSNA), which is accompanied by a profound pressor response in patients with impaired arterial baroreflex function and in older populations, but not in healthy young subjects. We tested the hypothesis that an enhancement in the gain of arterial baroreflex control of MSNA contributes to the maintenance of arterial blood pressure after water drinking in healthy young subjects. The MSNA, arterial blood pressure and heart rate were measured in 10 healthy men (24 ± 2 years old; mean ± SD) before and for 60 min after ingestion of 500 ml of bottled water or saline solution. Weighted linear regression analysis between MSNA and diastolic blood pressure was used to determine the gain (i.e. sensitivity) of arterial baroreflex control of MSNA. After water drinking, MSNA was significantly elevated within 15 min and remained above baseline for up to 60 min [e.g. 21 ± 10 bursts (100 heart beats)-1 mmHg-1 at baseline versus 35 ± 14 bursts (100 heart beats)-1 mmHg-1 at 30 min; P < 0.01], whereas mean arterial blood pressure (e.g. 87 ± 7 mmHg at baseline versus 89 ± 7 mmHg at 30 min; P = 0.34) and heart rate were unchanged. The arterial baroreflex-MSNA gain for bursts incidence was increased and remained elevated throughout the protocol [e.g. -2.25 ± 0.99 bursts (100 heart beats)-1 mmHg-1 at baseline versus -4.32 ± 1.53 bursts (100 heart beats)-1 mmHg-1 at 30 min; P < 0.01]. Importantly, saline intake had no effect on arterial baroreflex-MSNA gain or any neurocardiovascular variables. These findings demonstrate that water drinking enhances the gain of arterial baroreflex control of MSNA in healthy young men, which may contribute to buffering the pressor response after water drinking, probably via osmosensitive mechanisms.

NEW FINDINGS What is the central question of this study? We aimed to examine leg vascular responses to brief periods of inactivity. What is the main finding and its importance? We demonstrate that a mere 10 min of sitting is sufficient to impair leg microvascular function (reactive hyperaemia). However, conduit artery vasodilatation (flow-mediated dilatation) was unaffected, indicating maintained macrovascular function. Interestingly, immobile supine rest also resulted in a reduction in microvascular function alone that was prevented when calf muscle contractions were performed. Collectively, these data highlight the susceptibility of the microcirculation to short periods of inactivity and the beneficial role of skeletal muscle contraction for vascular health. ABSTRACT Prolonged sitting for 1-6 h has been shown to impair leg macrovascular [i.e. reduced flow-mediated dilatation (FMD)] and microvascular (i.e. reduced reactive hyperaemia) function. These impairments appear to be mediated through reductions in shear stress. Interestingly, a reduction in shear rate has been observed as early as 10 min into sitting. However, it is unknown whether this acute reduction in shear stress is sufficient to affect vascular function. Accordingly, we studied 18 young men and assessed popliteal artery FMD and reactive hyperaemia before (Baseline) and after (PostSit) a 10 min sitting period. Popliteal artery shear rate was significantly reduced during sitting (Baseline, 62 ± 35 s-1 ; 10 min sitting, 27 ± 13 s-1 ; P

© 2018 American Physiological Society. All rights reserved. As a primary component of homeostasis, the sympathetic nervous system enables rapid adjustments to stress through its ability to communicate messages among organs and cause targeted and graded end organ responses. Key in this communication model is the pattern of neural signals emanating from the central to peripheral components of the sympathetic nervous system. But what is the communication strategy employed in peripheral sympathetic nerve activity (SNA)? Can we develop and interpret the system of coding in SNA that improves our understanding of the neural control of the circulation? In 1968, Hagbarth and Vallbo (Hagbarth KE, Vallbo AB. Acta Physiol Scand 74: 96–108, 1968) reported the first use of microneurographic methods to record sympathetic discharges in peripheral nerves of conscious humans, allowing quantification of SNA at rest and sympathetic responsiveness to physiological stressors in health and disease. This technique also has enabled a growing investigation into the coding patterns within, and cardiovascular outcomes associated with, postganglionic SNA. This review outlines how results obtained by microneurographic means have improved our understanding of SNA outflow patterns at the action potential level, focusing on SNA directed toward skeletal muscle in conscious humans.

Blacks have the highest prevalence of hypertension, putting them at greater risk of cardiovascular disease and death. Previous studies have reported that, relative to whites, healthy black men have augmented pressor responses to sympathoexcitatory stressors. Although important, these studies do not inform about the resting state and the influence of spontaneous changes in resting muscle sympathetic nerve activity (MSNA). Likewise, little is known about the transduction of MSNA into a vascular response at rest on a beat-to-beat basis. Accordingly, we tested the hypothesis that relative to whites, blacks would exhibit greater vasoconstriction and pressor responses following spontaneous bursts of MSNA. Mean arterial pressure, common femoral artery blood flow, and MSNA were continuously recorded during 20 minutes of supine rest in 35 young healthy men (17 blacks and 18 whites). Signal averaging was used to characterize changes in leg vascular conductance, total vascular conductance, and mean arterial pressure following spontaneous MSNA bursts. Blacks demonstrated significantly greater decreases in leg vascular conductance (blacks: −15.0±1.0%; whites: −11.5±1.2%; P =0.042) and total vascular conductance (blacks: −8.6±0.9%; whites: −5.1±0.4%; P =0.001) following MSNA bursts, which resulted in greater mean arterial pressure increases (blacks: +5.2±0.6 mm Hg; whites: +3.9±0.3 mm Hg; P =0.04). These exaggerated responses in blacks compared with whites were present whether MSNA bursts occurred in isolation (singles) or in combination (multiples) and were graded with increases in burst height. Collectively, these findings suggest that healthy young black men exhibit augmented sympathetic vascular transduction at rest and provide novel insight into potential mechanism(s) by which this population may develop hypertension later in life.

Physical movement lasting any more than a few seconds (e.g., exercise), requires coordination of motor control with concomitant changes in the cardiovascular and respiratory support necessary to respond to the rapid increases in metabolic demand. Without such coordination, delivery of oxygen and removal of waste products become rate limiting and will restrict the duration, speed, and quality of movement. Fortunately, under healthy conditions, the central and peripheral nervous systems contribute importantly to this remarkable level of coordination via complex mechanisms that remain to be fully elucidated. The purposes of this review are to present the current state of knowledge regarding: (i) mechanisms by which the body maintains appropriate perfusion pressure to all organs during acute bouts of exercise, and (ii) alterations occurring in these mechanisms via central nervous system adaptations when exercise is performed or not performed on a regular basis (e.g., physically active versus sedentary lifestyle, respectively). Results from studies performed in humans and laboratory animals provide the reader a well-rounded knowledge base. They are intended to instill an appreciation of what is known, and not known, about how the brain regulates the cardiovascular system during acute bouts of exercise, and the adaptations that occur when individuals exercise regularly versus when chronically sedentary. Discussion of the latter is intended to provide novel mechanisms for the increased incidence of cardiovascular disease in sedentary individuals versus a reduced incidence in individuals who are regularly active. © 2018 American Physiological Society. Compr Physiol 8:103-151, 2018.

Atherosclerotic peripheral artery disease primarily manifests in the medium- to large-sized conduit arteries of the lower extremities. However, the factors underlying this increased vulnerability of leg macrovasculature to disease are largely unidentified. On the basis of recent studies, we propose that excessive time spent in the sitting position and the ensuing reduction in leg blood flow-induced shear stress cause endothelial cell dysfunction, a key predisposing factor to peripheral artery disease. In particular, this review summarizes the findings from laboratory-based sitting studies revealing acute leg vascular dysfunction with prolonged sitting in young healthy subjects, discusses the primary physiological mechanisms and the potential long-term implications of such leg vasculopathy with repeated exposure to prolonged sitting, as well as identifies strategies that may be effective at evading it.

Increased daily sitting time is associated with greater cardiovascular risk, and, on average, women are more sedentary than men. Recent reports have demonstrated that prolonged sitting reduces lower leg microvascular (reactive hyperemia) and macrovascular [flow-mediated dilation (FMD)] vasodilator function. However, these studies have predominately included men, and the effects of sitting in young women are largely unexplored. This becomes important given known sex differences in vascular function. Thus, herein, we assessed popliteal artery reactive hyperemia and FMD before and after a 3-h sitting period in healthy young women ( n = 12) and men ( n = 8). In addition, resting popliteal artery hemodynamics (duplex Doppler ultrasound) and calf circumference were measured before, during, and after sitting. Resting popliteal artery shear rate was reduced to a similar extent in both groups during the sitting period (women: −48.5 ± 8.4 s−1 and men: −52.9 ± 12.3 s−1, P = 0.45). This was accompanied by comparable increases in calf circumference in men and women ( P = 0.37). After the sitting period, popliteal artery FMD was significantly reduced in men (PreSit: 5.5 ± 0.9% and PostSit: 1.6 ± 0.4%, P < 0.001) but not women (PreSit: 4.4 ± 0.6% and PostSit: 3.6 ± 0.6%, P = 0.29). In contrast, both groups demonstrated similar reductions in hyperemic blood flow area under the curve (women: −28,860 ± 5,742 arbitrary units and men: −28,691 ± 9,685 arbitrary units, P = 0.99), indicating impaired microvascular reactivity after sitting. These findings indicate that despite comparable reductions in shear rate during 3 h of uninterrupted sitting, macrovascular function appears protected in some young women but the response was variable, whereas men exhibited more consistent reductions in FMD. In contrast, the leg microvasculature is susceptible to similar sitting-induced impairments in men and women. NEW & NOTEWORTHY We demonstrate that leg macrovascular function was consistently reduced in young men but not young women after prolonged sitting. In contrast, both men and women exhibited similar reductions in leg microvascular reactivity after sitting. These data demonstrate, for the first time, sex differences in vascular responses to prolonged sitting.

Recent evidence suggests that exposure of human monocytes to glucolipotoxic media to mimic the composition of plasma of patients with type 2 diabetes (T2D) results in the induction of endoplasmic reticulum stress markers and formation of reactive oxygen species (ROS). The extent to which these findings translate to patients with T2D remains unclear. Thus, we first measured ROS (dihydroethidium fluorescence) in peripheral blood mononuclear cells (PBMCs) from whole blood of T2D patients (n = 8) and compared to age matched healthy controls (n = 8). T2D patients exhibited greater basal intracellular ROS (mean±SD, +3.4 ± 1.4 fold; P

Increased endothelin-1 (ET-1) and reduced endothelial nitric oxide phosphorylation (peNOS) are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), but studies examining these links in humans are limited. We sought to assess basal and insulin-stimulated endothelial signaling proteins (ET-1 and peNOS) in skeletal muscle from T2D patients. Ten obese T2D [glucose disposal rate (GDR): 6.6 ± 1.6 mg·kg lean body mass (LBM)−1·min−1] and 11 lean insulin-sensitive subjects (Lean GDR: 12.9 ± 1.2 mg·kg LBM−1·min−1) underwent a hyperinsulinemic-euglycemic clamp with vastus lateralis biopsies taken before and 60 min into the clamp. Basal biopsies were also taken in 11 medication-naïve, obese, non-T2D subjects. ET-1, peNOS (Ser1177), and eNOS protein and mRNA were measured from skeletal muscle samples containing native microvessels. Femoral artery blood flow was assessed by duplex Doppler ultrasound. Insulin-stimulated blood flow was reduced in obese T2D (Lean: +50.7 ± 6.5% baseline, T2D: +20.8 ± 5.2% baseline, P < 0.05). peNOS/eNOS content was higher in Lean under basal conditions and, although not increased by insulin, remained higher in Lean during the insulin clamp than in obese T2D ( P < 0.05). ET-1 mRNA and peptide were 2.25 ± 0.50- and 1.52 ± 0.11-fold higher in obese T2D compared with Lean at baseline, and ET-1 peptide remained 2.02 ± 1.9-fold elevated in obese T2D after insulin infusion ( P < 0.05) but did not increase with insulin in either group ( P > 0.05). Obese non-T2D subjects tended to also display elevated basal ET-1 ( P = 0.06). In summary, higher basal skeletal muscle expression of ET-1 and reduced peNOS/eNOS may contribute to a reduced insulin-stimulated leg blood flow response in obese T2D patients.NEW & NOTEWORTHY Although impairments in endothelial signaling are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), human studies examining these links are limited. We provide the first measures of nitric oxide synthase and endothelin-1 expression from skeletal muscle tissue containing native microvessels in individuals with and without T2D before and during insulin stimulation. Higher basal skeletal muscle expression of endothelin-1 and reduced endothelial nitric oxide phosphorylation (peNOS)/eNOS may contribute to reduced insulin-stimulated blood flow in obese T2D patients.

Muscle sympathetic nerve activity (MSNA) decreases during leg cycling at low intensity because of muscle pump-induced increases in venous return and loading of the cardiopulmonary baroreceptors. However, MSNA increases during leg cycling when exercise is above moderate intensity or for a long duration, suggesting that the sympathoinhibitory effect of the cardiopulmonary baroreflex can be overridden by a powerful sympathoexcitatory drive, such as the skeletal muscle metaboreflex. Therefore, we tested the hypothesis that high-intensity muscle metaboreflex activation attenuates muscle pump-induced inhibition of MSNA during leg cycling. MSNA (left radial nerve) was recorded during graded isolation of the muscle metaboreflex in the forearm with postexercise ischemia (PEI) after low (PEI-L)- and high (PEI-H)-intensity isometric handgrip exercise (20% and 40% maximum voluntary contraction, respectively). Leg cycling (15–20 W) was performed alone and during each PEI trial (PEI-L+Cycling, PEI-H+Cycling). Cycling alone induced a significant decrease in MSNA burst frequency (BF) and total activity (TA). MSNA BF and TA also decreased when cycling was performed during PEI-L. However, the magnitude of decrease in MSNA during PEI-L+Cycling [∆BF: –19 ± 2% ( P < 0.001), ∆TA: –25 ± 4% ( P < 0.001); mean ± SE] was less than that during cycling alone [∆BF: –39 ± 5% ( P = 0.003), ∆TA: –45 ± 5% ( P = 0.002)]. More importantly, MSNA did not decrease during cycling with PEI-H [∆BF: –1 ± 2% ( P = 0.845), ∆TA: +2 ± 3% ( P = 0.959)]. These results suggest that muscle pump-induced inhibition of sympathetic vasomotor outflow during low-intensity leg cycling is attenuated by muscle metaboreflex activation in an intensity-dependent manner. NEW & NOTEWORTHY There are no available data concerning the interaction between the sympathoinhibitory effect of muscle pump-induced cardiopulmonary baroreflex loading during leg cycling and the sympathoexcitatory influence of the muscle metaboreflex. In this study, muscle metaboreflex activation attenuated the inhibition of muscle sympathetic nerve activity (MSNA) during leg cycling. This may explain, in part, the response of MSNA to graded-intensity dynamic exercise in which low-intensity leg cycling inhibits MSNA whereas high-intensity exercise elicits graded sympathoexcitation.

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide that is upregulated in obesity. Herein, we tested the hypothesis that ET-1 signaling promotes visceral adipose tissue (AT) inflammation and disrupts glucose homeostasis. We also tested if reduced ET-1 is a required mechanism by which exercise ameliorates AT inflammation and improves glycemic control in obesity. We found that 1) diet-induced obesity, AT inflammation, and glycemic dysregulation were not accompanied by significantly increased levels of ET-1 in AT or circulation in wild-type mice and that endothelial overexpression of ET-1 and consequently increased ET-1 levels did not cause AT inflammation yet impaired glucose tolerance; 2) reduced AT inflammation and improved glucose tolerance with voluntary wheel running was not associated with decreased levels of ET-1 in AT or circulation in obese mice nor did endothelial overexpression of ET-1 impede such exercise-induced metabolic adaptations; 3) chronic pharmacological blockade of ET-1 receptors did not suppress AT inflammation in obese mice but improved glucose tolerance; and 4) in a cohort of human subjects with a wide range of body mass indexes, ET-1 levels in AT, or circulation were not correlated with markers of inflammation in AT. In aggregate, we conclude that ET-1 signaling is not implicated in the development of visceral AT inflammation but promotes glucose intolerance, thus representing an important therapeutic target for glycemic dysregulation in conditions characterized by hyperendothelinemia. Furthermore, we show that the salutary effects of exercise on AT and systemic metabolic function are not contingent on the suppression of ET-1 signaling.

New findings What is the topic of this review? This review summarizes and synthesizes what is known about the contribution of inflammation to age-related arterial dysfunction. What advances does it highlight? This review details observational evidence for the relationship of age-related inflammation and arterial dysfunction, insight from autoimmune inflammatory diseases and their effects on arterial function, interventional evidence linking inflammation and age-related arterial dysfunction, insight into age-related arterial inflammation from preclinical models and interventions to ameliorate age-related inflammation and arterial dysfunction. Abstract Advanced age is a primary risk factor for cardiovascular disease, the leading cause of death in the industrialized world. Two major components of arterial ageing are stiffening of the large arteries and impaired endothelium-dependent dilatation in multiple vascular beds. These two alterations are major contributors to the development of overt cardiovascular disease. Increasing inflammation with advanced age is likely to play a role in this arterial dysfunction. The purpose of this review is to synthesize what is known about inflammation and its relationship to age-related arterial dysfunction. This review discusses both the initial observational evidence for the relationship of age-related inflammation and arterial dysfunction and the evidence that inflammatory autoimmune diseases are associated with a premature arterial ageing phenotype. We next discuss interventional and mechanistic evidence linking inflammation and age-related arterial dysfunction in older adults. We also attempt to summarize the relevant evidence from preclinical models. Lastly, we discuss interventions in both humans and animals that have been shown to ameliorate age-related arterial inflammation and dysfunction. The available evidence provides a strong basis for the role of inflammation in both large artery stiffening and impairment of endothelium-dependent dilatation; however, the specific inflammatory mediators, the initiating factors and the relative importance of the endothelium, smooth muscle cells, perivascular adipose tissue and immune cells in arterial inflammation are not well understood. With the expansion of the ageing population, ameliorating age-related arterial inflammation represents an important potential strategy for preserving vascular health in the elderly.

In addition to its metabolic actions, insulin stimulates peripheral vasodilation, which serves to increase glucose delivery to skeletal muscle. Indeed, insulin-stimulated increases in muscle blood ...