Developed in 1992, the flow-mediated dilation test is now the most commonly used noninvasive assessment of vascular endothelial function in humans. Since its inception, scientists have refined their ...understanding of the physiology, analysis, and interpretation of this measurement. Recently, a significant growth of knowledge has added to our understanding and implementation of this clinically relevant research methodology. Therefore, this tutorial provides timely insight into recent advances and practical information related to the ultrasonic assessment of vascular endothelial function in humans.
Endothelial dysfunction is now considered an important early event in the development of atherosclerosis, which precedes gross morphological signs and clinical symptoms. The assessment of ...flow-mediated dilation (FMD) was introduced almost 20 years ago as a noninvasive approach to examine vasodilator function in vivo. FMD is widely believed to reflect endothelium-dependent and largely nitric oxide-mediated arterial function and has been used as a surrogate marker of vascular health. This noninvasive technique has been used to compare groups of subjects and to evaluate the impact of interventions within individuals. Despite its widespread adoption, there is considerable variability between studies with respect to the protocols applied, methods of analysis, and interpretation of results. Moreover, differences in methodological approaches have important impacts on the response magnitude, can result in spurious data interpretation, and limit the comparability of outcomes between studies. This review results from a collegial discussion between physiologists with the purpose of developing considered guidelines. The contributors represent several distinct research groups that have independently worked to advance the evidence base for improvement of the technical approaches to FMD measurement and analysis. The outcome is a series of recommendations on the basis of review and critical appraisal of recent physiological studies, pertaining to the most appropriate methods to assess FMD in humans.
Abstract
Context
Type 1 diabetes (T1D) negatively affects both the endothelin system and muscle oxidative capacity. The endothelin pathway is a critical regulator of microcirculatory function and may ...exhibit sexual dichotomy by which healthy premenopausal women have greater endothelin-B receptor (ETBR) function compared to men. Moreover, T1D may differentially alter muscle oxidative capacity in men and women; however, whether ETBR function is impaired in women compared to men with T1D and its relationship with muscle oxidative capacity has yet to be explored.
Objective
The purpose of this investigation was to determine if ETBR-mediated dilation is impaired in women compared to men with T1D and if this is related to their skeletal muscle oxidative capacity.
Methods
Men (n = 9; glycated hemoglobin A1c HbA1c = 7.8 ± 1.0%) and women (N = 10 women; HbA1c = 8.4 ± 1.3%) with uncomplicated T1D were recruited for this investigation. Near-infrared spectroscopy (NIRS) and intradermal microdialysis (750 nM BQ-123 + ET-1 10−20–10−8 mol/L) were used to evaluate skeletal muscle oxidative capacity and assess ETBR-mediated vasodilation, respectively.
Results
Skeletal muscle oxidative capacity was significantly lower (P = .031) in women compared with men with T1D. However, ETBR-mediated dilation induced a significantly greater (P = .012) vasodilatory response in women compared to men with T1D, and the area under the curve was negatively associated with skeletal muscle oxidative capacity (r = −.620; P = .042).
Conclusion
Compared to men with uncomplicated T1D, muscle oxidative capacity was lower and ETBR-mediated vasodilation was higher in women with uncomplicated T1D. ETBR-induced vasodilatory capacity was inversely related to skeletal muscle oxidative capacity, suggesting there may be compensatory mechanisms occurring to preserve microvascular blood flow in women with T1D.
Cholesterol is a foundational molecule of biology. There is a long-standing interest in understanding how cholesterol metabolism is intertwined with cancer biology. In this review, we focus on the ...known connections between lung cancer and molecules mediating cholesterol efflux. A major take-home lesson is that the roles of many cholesterol efflux factors remain underexplored. It is our hope that this article would motivate others to investigate how cholesterol efflux factors contribute to lung cancer biology.
This paper describes the main results from an experimental investigation into the consequences of deformation twinning in AZ31 on various aspects of plastic deformation, including the anisotropic ...strain-hardening rates, the tension/compression yield asymmetry, and the evolution of crystallographic texture. It was seen that AZ31 exhibited unusually high normalized strain-hardening rates compared to α-Ti that occurred beyond the strain levels where extension twins have completely altered the underlying texture. This observation challenges the validity of the generally accepted notion in the current literature that the high strain-hardening rates in AZ31 are directly caused by extension twins. It is postulated here that the thin contraction twins are very effective in strain hardening of the alloy by restricting the slip length associated with pyramidal 〈c+a〉 slip. This new hypothesis is able to explain the major experimental observations made in this study and in the prior literature. We have also presented a new hypothesis for the physical origin of the observed differences in the thicknesses of the extension and contraction twins. The stress fields in selected matrix–twin configurations were modeled using crystal plasticity finite element models. The contraction twin (01¯11)01¯12¯ was predicted to form an internal extension twin (011¯2)01¯11, resulting in the commonly observed “double twin” sequence. The extension twin is suggested to inhibit thickening of this double twin by loss of twin–matrix coherency. Extension twins were predicted to retain their coherency and thus thicken.
Exosomes, key mediators of cell‐cell communication, derived from type 2 diabetes mellitus (T2DM) exhibit detrimental effects. Exercise improves endothelial function in part via the secretion of ...exosomes into circulation. Extracellular superoxide dismutase (SOD3) is a major secretory copper (Cu) antioxidant enzyme that catalyzes the dismutation of O2•− to H2O2 whose activity requires the Cu transporter ATP7A. However, the role of SOD3 in exercise‐induced angiogenic effects of circulating plasma exosomes on endothelial cells (ECs) in T2DM remains unknown. Here, we show that both SOD3 and ATP7A proteins were present in plasma exosomes in mice, which was significantly increased after two weeks of volunteer wheel exercise. A single bout of exercise in humans also showed a significant increase in SOD3 and ATP7A protein expression in plasma exosomes. Plasma exosomes from T2DM mice significantly reduced angiogenic responses in human ECs or mouse skin wound healing models, which was associated with a decrease in ATP7A, but not SOD3 expression in exosomes. Exercise training in T2DM mice restored the angiogenic effects of T2DM exosomes in ECs by increasing ATP7A in exosomes, which was not observed in exercised T2DM/SOD3−/− mice. Furthermore, exosomes overexpressing SOD3 significantly enhanced angiogenesis in ECs by increasing local H2O2 levels in a heparin‐binding domain‐dependent manner as well as restored defective wound healing and angiogenesis in T2DM or SOD3−/− mice. In conclusion, exercise improves the angiogenic potential of circulating exosomes in T2DM in a SOD3‐dependent manner. Exosomal SOD3 may provide an exercise mimetic therapy that supports neovascularization and wound repair in cardiometabolic disease.
Circadian rhythm regulates many important biological functions in humans. The goal of this study is to explore the impact of day-to-day deviations in the sleep-wake cycle on nighttime blood pressure ...(BP) dipping and further examine whether the ethnic difference in day-to-day deviations in sleep patterns can explain the ethnic difference in nighttime BP dipping.
Twenty-four-hour ambulatory BP monitoring and 7-day accelerometer data were obtained from 365 adult participants (age range, 18.7-50.1 years; 52.6% Black participants and 47.3% European Americans; 64.1% females). Systolic BP dipping level was used to represent nighttime BP dipping. The SD of sleep duration was calculated as the index of sleep variability, and the SD of sleep midpoint was calculated as the index of sleep irregularity.
A 1-hour increase in the SD of sleep midpoint was associated with a 1.16% decrease in nighttime BP dipping (
<0.001). A 1-hour increase in the SD of sleep duration was associated with a 1.39% decrease in nighttime BP dipping (
=0.017). The ethnic difference in the SD of sleep midpoint can explain 29.2% of the ethnicity difference in BP dipping (
=0.008).
Sleep variability and sleep irregularity are associated with blunted BP dipping in the general population. In addition, data from the present investigation also demonstrate that the ethnic difference in sleep irregularity could partly explain the ethnic difference in BP dipping, an important finding that may help reduce the health disparity between Black participants and European Americans.
New Findings
What is the topic of this review?
This review highlights the central and peripheral mechanisms that alter oxygen transport and utilisation and thereby contribute to exercise limitation ...in people with cystic fibrosis, considering also viable therapeutic targets for intervention.
What advances does it highlight?
Although traditionally considered a respiratory condition, pathological intramuscular and cardiovascular changes in people with cystic fibrosis appear to be key determinants of exercise intolerance up until the later stages of respiratory disease. Even young, habitually active patients with normal lung function experience multisystemic abnormalities, which play a role in exercise intolerance.
Cystic fibrosis (CF) is a complex condition, commonly associated with exercise limitation. The mechanisms responsible for this in CF are of interest, given that lower aerobic fitness is associated with an increased risk of being hospitalised with pulmonary exacerbation, a poorer quality of life and a poorer prognosis. Pathophysiological changes in lung function are considered central to CF, and may contribute to exercise limitation. However, it is now clear that the pathogenesis of exercise limitation in this population is multifactorial, with alterations in cardiovascular, muscle and pulmonary function contributing. Whilst some of these changes are attributable to respiratory disease per se, the CF transmembrane conductance regulator protein is also found in skeletal muscle and the vascular endothelium and can directly alter central and localised oxygen delivery, as well as the ability to effectively extract and utilise oxygen at the myocyte level. Since intense exercise poses considerable challenges to arterial oxygen content and/or blood flow and its supply to the working skeletal muscle, evaluating the exercise physiology of people with CF has helped us understand the mechanisms underlying exercise intolerance. Through several investigations over recent years, we have collectively demonstrated that people with CF exhibit reduced skeletal muscle oxygen extraction and utilisation during exercise, with a lesser contribution from haemodynamic or chronotropic mechanisms. Taken together, our findings highlight the importance of targeting mechanisms of skeletal muscle oxygen utilisation in CF to improve exercise tolerance and we offer potential therapeutic interventional strategies.
Background
The endothelin system has been identified as a key regulator of vascular function and is comprised of two receptors; a constricting A‐receptor (ETAR) and dilating B‐receptor (ETBR). Sex ...differences in the ET‐1 pathway have been established. Specifically, when compared to men, activation of the ETBR in women results in a favorable dilatory response. In the presence of diabetes; however, the endothelin system in general, is negatively altered. Whether sex differences in the endothelin pathway are observed in type 1 diabetes (T1D), is unknown. Thus, the present investigation sought to test the hypothesis that ETB receptor function is reduced in women with T1D compared to men with T1D.
Methods
Premenopausal women (n=2, HbA1c=10.4±0.8%, age=29±13 years, BMI=29.9±2.8 kg/m2) and men (n=4, HbA1c=8.5±1.0%, age=22±3 years, BMI=21.5±2.8 kg/m2) with a clinical diagnosis of T1D were recruited to participate. Three microdialysis fibers were inserted into the dermal layer of the right forearm where cutaneous blood flow was measured using laser speckle contrast imaging. Microvascular function was determined by a ten dose incremental perfusion of acetylcholine (Ach; 10‐2‐2*103 M). Endothelin receptor function was determined two ways: 1) by a seven dose incremental perfusion of ET‐1 (10‐20‐10‐8 M), and 2) by a seven dose incremental perfusion of ET‐1 (10‐20‐10‐8 M) combined with the selective ETAR antagonist, BQ‐123 (750 nM). The dose response area under the curve (AUC) for cutaneous vascular conductance of each fiber was calculated for each individual.
Results
Women with T1D had a significantly greater BMI (p=0.026) and HbA1C(p=0.089) compared to men with T1D. The Ach dose response AUC was greater (p=0.135) in women with T1D (753.5±12.7 AU) when compared to men with T1D (691.7±61.1 AU). The ET‐1 + BQ‐123 dose response AUC tended (p=0.298) to be lower in women with T1D (295.5±14.1 AU) when compared to men with T1D (357.8±98.6 AU). A similar lower response in women was observed for the ET‐1 AUC (p=0.102; men: 1411.9±508.9 AU vs women: 821.7±38.5 AU).
Conclusion
These data suggest that, compared to men with T1D, microvascular function is greater in women, albeit weighing more and having a higher HbA1c. In contrast, preliminary findings indicate that ETBR function may be impaired in women with T1D compared to men with T1D.
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