Non-pharmacological interventions for vascular health and the role of the endothelium.

The most common non-pharmacological intervention for both peripheral and cerebral vascular health is regular physical activity (e.g., exercise training), which improves function across a range of exercise intensities and modalities. Numerous non-exercising approaches have also been suggested to improved vascular function, including repeated ischemic preconditioning (IPC); heat therapy such as hot water bathing and sauna; and pneumatic compression. Chronic adaptive responses have been observed across a number of these approaches, yet the precise mechanisms that underlie these effects in humans are not fully understood. Acute increases in blood flow and circulating signalling factors that induce responses in endothelial function are likely to be key moderators driving these adaptations. While the impact on circulating factors and environmental mechanisms for adaptation may vary between approaches, in essence, they all centre around acutely elevating blood flow throughout the circulation and stimulating improved endothelium-dependent vascular function and ultimately vascular health. Here, we review our current understanding of the mechanisms driving endothelial adaptation to repeated exposure to elevated blood flow, and the interplay between this response and changes in circulating factors. In addition, we will consider the limitations in our current knowledge base and how these may be best addressed through the selection of more physiologically relevant experimental models and research. Ultimately, improving our understanding of the unique impact that non-pharmacological interventions have on the vasculature will allow us to develop superior strategies to tackle declining vascular function across the lifespan, prevent avoidable vascular-related disease, and alleviate dependency on drug-based interventions.

Do acute effects of exercise on vascular function predict adaptation to training?

PURPOSE: No previous study has explored the importance of exercise-induced changes in vascular function to prolonged adaptations. Therefore, the purpose was to explore the within-subject relationship between the acute post-exercise change in brachial artery endothelial function (flow-mediated dilation, FMD) and the change in resting FMD after a 2-week exercise training in healthy volunteers. METHODS: Twenty one healthy, young men (24 ± 5 years) underwent assessment of brachial artery FMD using high-resolution ultrasound before and after 30-min of moderate-intensity cycle exercise (80% maximal heart rate). Subsequently, subjects performed five 30-min cycle exercise bouts at 80% maximal heart rate across a 2-week period, followed by repeat assessment of resting brachial FMD post-training. RESULTS: Correcting for changes in diameter and shear, FMD did not change after the initial exercise bout (P = 0.26). However, a significant correlation was found between post-exercise changes in FMD and adaptation in resting FMD after training (r = 0.634, P = 0.002), where an acute decrease in post-exercise FMD resulted in a decrease in baseline FMD after 2 weeks and vice versa. We also found a positive correlation between antegrade shear rate during exercise and change in FMD% after acute exercise and after exercise training (r = 0.529 and 0.475, both P < 0.05). CONCLUSION: Our findings suggest that acute post-exercise changes in vascular function are related to changes in resting FMD after a 2-week endurance exercise training period in healthy men, an effect that may be related to exercise-induced increases in antegrade shear rate. This provides further insight into the relevance of acute changes in shear and FMD for subsequent adaptation.

Localised cutaneous microvascular adaptation to exercise training in humans.

PURPOSE: Exercise training induces adaptation in conduit and resistance arteries in humans, partly as a consequence of repeated elevation in blood flow and shear stress. The stimuli associated with intrinsic cutaneous microvascular adaptation to exercise training have been less comprehensively studied. METHODS: We studied 14 subjects who completed 8-weeks cycle ergometer training, with partial cuff inflation on one forearm to unilaterally attenuate cutaneous blood flow responses during each exercise-training bout. Before and after training, bilateral forearm skin microvascular dilation was determined using cutaneous vascular conductance (CVC: skin flux/blood pressure) responses to gradual localised heater disk stimulation performed at rest (33, 40, 42 and 44 °C). RESULTS: Cycle exercise induced significant increases in forearm cutaneous flux and temperature, which were attenuated in the cuffed arm (2-way ANOVA interaction-effect; P < 0.01). We found that forearm CVC at 42 and 44 °C was significantly lower in the uncuffed arm following 8-weeks of cycle training (P < 0.01), whereas no changes were apparent in the contralateral cuffed arm (P = 0.77, interaction-effect P = 0.01). CONCLUSIONS: Lower limb exercise training in healthy young men leads to lower CVC-responses to a local heating stimulus, an adaptation mediated, at least partly, by a mechanism related to episodic increases in skin blood flow and/or skin temperature.

Exercise training reduces the acute physiological severity of post-menopausal hot flushes.

KEY POINTS: A post-menopausal hot flush consists of profuse physiological elevations in cutaneous vasodilatation and sweating that are accompanied by reduced brain blood flow. These responses can be used to objectively quantify hot flush severity. The impact of an exercise training intervention on the physiological responses occurring during a hot flush is currently unknown. In a preference-controlled trial involving 21 post-menopausal women, 16 weeks of supervised moderate intensity exercise training was found to improve cardiorespiratory fitness and attenuate cutaneous vasodilatation, sweating and the reductions in cerebral blood flow during a hot flush. It is concluded that the improvements in fitness that are mediated by 16 weeks of exercise training reduce the severity of physiological symptoms that occur during a post-menopausal hot flush. A hot flush is characterised by feelings of intense heat, profuse elevations in cutaneous vasodilatation and sweating, and reduced brain blood flow. Exercise training reduces self-reported hot flush severity, but underpinning physiological data are lacking. We hypothesised that exercise training attenuates the changes in cutaneous vasodilatation, sweat rate and cerebral blood flow during a hot flush. In a preference trial, 18 symptomatic post-menopausal women underwent a passive heat stress to induce hot flushes at baseline and follow-up. Fourteen participants opted for a 16 week moderate intensity supervised exercise intervention, while seven participants opted for control. Sweat rate, cutaneous vasodilatation, blood pressure, heart rate and middle cerebral artery velocity (MCAv) were measured during the hot flushes. Data were binned into eight equal segments, each representing 12.5% of hot flush duration. Weekly self-reported frequency and severity of hot flushes were also recorded at baseline and follow-up. Following training, mean hot flush sweat rate decreased by 0.04 mg cm(2) min(-1) at the chest (95% confidence interval 0.02-0.06, P = 0.01) and by 0.03 mg cm(2) min(-1) (0.02-0.05, P = 0.03) at the forearm, compared with negligible changes in control. Training also mediated reductions in cutaneous vasodilatation by 9% (6-12%) at the chest and by 7% (4-9%) at forearm (P ≤ 0.05). Training attenuated hot flush MCAv by 3.4 cm s(-1) (0.7-5.1 cm s(-1) , P = 0.04) compared with negligible changes in control. Exercise training reduced the self-reported severity of hot flushes by 109 arbitrary units (80-121, P < 0.001). These data indicate that exercise training leads to parallel reductions in hot flush severity and within-flush changes in cutaneous vasodilatation, sweating and cerebral blood flow.

Repeated ischaemic preconditioning: a novel therapeutic intervention and potential underlying mechanisms.

What is the topic of this review? This review discusses the effects of repeated exposure of tissue to ischaemic preconditioning on cardiovascular function, the attendant adaptations and their potential clinical relevance. What advances does it highlight? We discuss the effects of episodic exposure to ischaemic preconditioning to prevent and/or attenuate ischaemic injury and summarize evidence pertaining to improvements in cardiovascular function and structure. Discussion is provided regarding the potential mechanisms that contribute to both local and systemic adaptation. Findings suggest that clinical benefits result from both the prevention of ischaemic events and the attenuation of their consequences. Ischaemic preconditioning (IPC) refers to the phenomenon whereby short periods of cyclical tissue ischaemia confer subsequent protection against ischaemia-induced injury. As a consequence, IPC can ameliorate the myocardial damage following infarction and can reduce infarct size. The ability of IPC to confer remote protection makes IPC a potentially feasible cardioprotective strategy. In this review, we discuss the concept that repeated exposure of tissue to IPC may increase the 'dose' of protection and subsequently lead to enhanced protection against ischaemia-induced myocardial injury. This may be relevant for clinical populations, who demonstrate attenuated efficacy of IPC to prevent or attenuate ischaemic injury (and therefore myocardial infarct size). Furthermore, episodic IPC facilitates repeated exposure to local (e.g. shear stress) and systemic stimuli (e.g. hormones, cytokines, blood-borne substances), which may induce improvement in vascular function and health. Such adaptation may contribute to prevention of cardio- and cerebrovascular events. The clinical benefits of repeated IPC may, therefore, result from both the prevention of ischaemic events and the attenuation of their consequences. We provide an overview of the literature pertaining to the impact of repeated IPC on cardiovascular function, related to both local and remote adaptation, as well as potential clinical implications.

Interval exercise, but not endurance exercise, prevents endothelial ischemia-reperfusion injury in healthy subjects.

Endothelial ischemia-reperfusion (I/R) injury importantly contributes to the poor prognosis during ischemic (myocardial) events. Preconditioning, i.e., repeated exposure to short periods of ischemia, effectively reduces endothelial I/R injury. In the present study, we examined the hypothesis that exercise has preconditioning effects on endothelial I/R injury. Therefore, we studied whether an acute bout of endurance or interval exercise is able to protect against endothelial I/R injury. In 17 healthy young subjects, we examined changes in brachial artery endothelial function using flow-mediated dilation (FMD) before and after a bout of high-intensity interval exercise, moderate-intensity endurance exercise, or a control intervention. Subsequently, I/R injury was induced by inflation of a blood pressure cuff around the upper arm to 220 mmHg for 20 min and 20 min of reperfusion followed by another FMD measurement. Near-infrared spectrometry was used to examine local tissue oxygenation during exercise. No differences in brachial artery FMD were found at baseline for the three conditions. I/R induced a significant decline in FMD (7.1±2.3 to 4.3±2.3, P<0.001). When preceded by the interval exercise bout, no change in FMD was present after I/R (7.7±3.1 to 7.2±3.1, P=0.56), whereas the decrease in FMD after I/R could not be prevented by the endurance exercise bout (7.8±3.1 to 3.8±1.7, P<0.001). In conclusion, a single bout of lower limb interval exercise, but not moderate-intensity endurance exercise, effectively prevents brachial artery endothelial I/R injury. This indicates the presence of a remote preconditioning effect of exercise, which is selectively present after short-term interval but not continuous exercise in healthy young subjects.

Exercise training reverses endothelial dysfunction in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease (CVD). Endothelial dysfunction is an early manifestation of atherosclerosis and an important prognostic marker for future cardiovascular events. The aim of this study was twofold: to examine 1) the association between liver fat, visceral adipose tissue (VAT), and endothelial dysfunction in obese NAFLD patients and 2) the impact of supervised exercise training on this vascular defect. Brachial artery endothelial function was assessed by flow-mediated dilatation (FMD) in 34 obese NAFLD patients and 20 obese controls of similar age and cardiorespiratory fitness [peak oxygen uptake (V̇o2 peak)] (48 ± 2 vs. 47 ± 2 yr; 27 ± 1 vs. 26 ± 2 ml·kg−1·min−1−1). Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively. Twenty-one NAFLD patients completed either 16 wk of supervised moderate-intensity exercise training (n = 13) or conventional care (n = 8). Differences between NAFLD and controls were compared using independent t-tests and effects of interventions by analysis of covariance. NAFLD patients had higher liver fat [11.6% (95% CI = 7.4, 18.1), P < 0.0005] and VAT [1.6 liters (95% CI = 1.2, 2.0), P < 0.0001] than controls and exhibited impaired FMD compared with controls [−3.6% (95% CI = −4.9, −2.2), P < 0.0001]. FMD was inversely correlated with VAT (r = −0.54, P = 0.001) in NAFLD, although the impairment in FMD remained following covariate adjustment for VAT [3.1% (95% CI = 1.8, 4.5), P < 0.001]. Exercise training, but not conventional care, significantly improved V̇o2 peak [9.1 ml·kg−1·min−1 (95% CI = 4.1, 14.1); P = 0.001] and FMD [3.6% (95% CI = 1.6, 5.7), P = 0.002]. Endothelial dysfunction in NAFLD cannot be fully explained by excess VAT but can be reversed with exercise training; this has potential implications for the primary prevention of CVD in NAFLD.

Endothelial dysfunction in hyperandrogenic polycystic ovary syndrome is not explained by either obesity or ectopic fat deposition.

PCOS (polycystic ovary syndrome) is associated with IR (insulin resistance), increased visceral fat and NAFLD (non-alcoholic fatty liver disease) all of which may contribute to endothelial dysfunction, an early marker of CVD (cardiovascular disease) risk. Our objective was to examine the relationships between endothelial dysfunction in PCOS, the volume of AT (adipose tissue) compartments and the size of intracellular TAG (triacylglycerol) pools in liver and skeletal muscle. A total of 19 women with PCOS (means±S.D.; 26±6 years, 36±5 kg/m2) and 16 control women (31±8 years, 30±6 kg/m2) were recruited. Endothelial function was assessed in the brachial artery using FMD (flow-mediated dilation). VAT (visceral AT) and abdominal SAT (subcutaneous AT) volume were determined by whole body MRI, and liver and skeletal muscle TAG by 1H-MRS (proton magnetic resonance spectroscopy). Cardiorespiratory fitness and HOMA-IR (homoeostasis model assessment of IR) were also determined. Differences between groups were analysed using independent Student's t tests and ANCOVA (analysis of co-variance). FMD was impaired in PCOS by 4.6% [95% CI (confidence interval), 3.0-7.7; P<0.001], and this difference decreased only slightly to 4.2% (95% CI, 2.4-6.1; P<0.001) when FMD was adjusted for individual differences in visceral and SAT and HOMA-IR. This magnitude of impairment was also similar in lean and obese PCOS women. The results suggest that endothelial dysfunction in PCOS is not explained by body fat distribution or volume. FMD might be a useful independent prognostic tool to assess CVD risk in this population.

Exercise training improves cutaneous microvascular function in nonalcoholic fatty liver disease.

The leading causes of mortality in nonalcoholic fatty liver disease (NAFLD) relate to cardiovascular disease (CVD). The contribution of nitric oxide (NO) to endothelial function, a surrogate of CVD risk, is currently unknown in NAFLD. We hypothesize that NO-mediated cutaneous microvessel function would be impaired in NAFLD compared with controls and that exercise would enhance microvessel function compared with conventional care. Thirteen NAFLD patients (aged 50 ± 3 yr, BMI 31 ± 1 kg/m²) and seven controls (48 ± 4 yr, 30 ± 2 kg/m²) were studied. NAFLD patients were randomized to either 16 wk of exercise or conventional care. Cutaneous microvessel function was examined using laser Doppler flowmetry combined with intradermal microdialysis of N(G)-monomethyl-l-arginine to assay the NO dilator response to local forearm heating. Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively, and cardiorespiratory fitness was assessed. Differences in NO contribution to cutaneous blood flow between NAFLD and control individuals and between interventions were analyzed using general linear modeling. NO contribution to cutaneous blood flow was similar between NAFLD and controls (P = 0.47). Cardiorespiratory fitness was greater following exercise training compared with conventional care. NO contribution to cutaneous blood flow in response to heating at 42°C was 20.4% CVCmax (95% CI = 4.4, 36.4) greater following exercise training compared with conventional care (P = 0.02). Exercise training improves cutaneous microvascular NO function in NAFLD patients. The benefit of exercise training compared with conventional care strongly supports a role for exercise in the prevention of CVD in NAFLD.

Endothelial function measured using flow-mediated dilation in polycystic ovary syndrome: a meta-analysis of the observational studies.

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) demonstrate an increased prevalence of cardiovascular disease (CVD) risk factors. Previous researchers have compared flow-mediated dilation (FMD), an early marker of CVD, in women with and without PCOS. Evidence for a PCOS-mediated reduction in FMD remains equivocal, potentially because of study differences in cohort-matching and measurement approaches. The aims of this systematic review and meta-analysis were to examine to what extent FMD is impaired in PCOS and to explore the influence of potential moderators of FMD reduction, such as age and BMI. DESIGN: A systematic review and meta-analysis of published observational studies comparing FMD in PCOS with control women. PATIENTS: Twenty-one published studies were included (PCOS, n = 908; controls, n = 566). A subanalysis, using tighter inclusion criteria, involved seven studies (PCOS, n = 402; control, n = 251). MEASUREMENTS: Mean differences in FMD between PCOS and controls were synthesized. The subanalysis was delimited to the inclusion of age and BMI-matched controls. These factors were then explored as moderators using meta-regression. RESULTS: The pooled mean FMD was 3.4% (95% CI=1.9, 4.9) lower in PCOS compared with control women, with substantial heterogeneity between studies. In the subanalysis, the PCOS-mediated reduction in FMD was 4.1% (95% CI=2.7, 5.5). Heterogeneity remained substantial (I(2) =81%). Subsequent meta-regression indicated that the magnitude of FMD difference was not influenced by BMI (P = 0.17) nor age (P = 0.38). CONCLUSIONS: This systematic research synthesis indicates that endothelial function is compromised in PCOS women, even if they are young and nonobese.

Remote ischemic preconditioning prevents reduction in brachial artery flow-mediated dilation after strenuous exercise.

Strenuous exercise is associated with an immediate decrease in endothelial function. Repeated bouts of ischemia followed by reperfusion, known as remote ischemic preconditioning (RIPC), is able to protect the endothelium against ischemia-induced injury beyond the ischemic area. We examined the hypothesis that RIPC prevents the decrease in endothelial function observed after strenuous exercise in healthy men. In a randomized, crossover study, 13 healthy men performed running exercise preceded by RIPC of the lower limbs (4 × 5-min 220-mmHg bilateral occlusion) or a sham intervention (sham; 4 × 5-min 20-mmHg bilateral occlusion). Participants performed a graded maximal treadmill running test, followed by a 5-km time trial (TT). Brachial artery endothelial function was examined before and after RIPC or sham, as well as after the 5-km TT. We measured flow-mediated dilation (FMD), an index of endothelium-dependent function, using high-resolution echo-Doppler. We also calculated the shear rate area-under-the-curve (from cuff deflation to peak dilatation; SR(AUC)). Data are described as mean and 95% confidence intervals. FMD changed by <0.6% immediately after both ischemic preconditioning (IPC) and sham interventions (P > 0.30). In the sham trial, FMD changed from 5.1 (4.4-5.9) to 3.7% (2.6-4.8) following the 5-km TT (P = 0.02). In the RIPC trial, FMD changed negligibly from 5.4 (4.4-6.4) post-IPC and 5.7% (4.6-6.8) post 5-km TT (P = 0.60). Baseline diameter, SR(AUC), and time-to-peak diameter were all increased following the 5-km TT (P < 0.05), but these changes did not influence the IPC-mediated maintenance of FMD. In conclusion, these data indicate that strenuous lower-limb exercise results in an acute decrease in brachial artery FMD of ~1.4% in healthy men. However, we have shown for the first time that prior RIPC of the lower limbs maintains postexercise brachial artery endothelium-dependent function at preexercise levels.

Impact of exercise training on arterial wall thickness in humans.

Thickening of the carotid artery wall has been adopted as a surrogate marker of pre-clinical atherosclerosis, which is strongly related to increased cardiovascular risk. The cardioprotective effects of exercise training, including direct effects on vascular function and lumen dimension, have been consistently reported in asymptomatic subjects and those with cardiovascular risk factors and diseases. In the present review, we summarize evidence pertaining to the impact of exercise and physical activity on arterial wall remodelling of the carotid artery and peripheral arteries in the upper and lower limbs. We consider the potential role of exercise intensity, duration and modality in the context of putative mechanisms involved in wall remodelling, including haemodynamic forces. Finally, we discuss the impact of exercise training in terms of primary prevention of wall thickening in healthy subjects and remodelling of arteries in subjects with existing cardiovascular disease and risk factors.

Time course of arterial remodelling in diameter and wall thickness above and below the lesion after a spinal cord injury.

Physical inactivity in response to a spinal cord injury (SCI) represents a potent stimulus for conduit artery remodelling. Changes in conduit artery characteristics may be induced by the local effects of denervation (and consequent extreme inactivity below the level of the lesion), and also by systemic adaptations due to whole body inactivity. Therefore, we assessed the time course of carotid (i.e. above lesion) and common femoral artery (i.e. below lesion) lumen diameter and wall thickness across the first 24 weeks after an SCI. Eight male subjects (mean age 35 ± 14 years) with a traumatic motor complete spinal cord lesion between T5 and L1 (i.e. paraplegia) were included. Four subjects were measured across the first 6 weeks after SCI, whilst another four subjects were measured from 8 until 24 weeks after SCI. Ultrasound was used to examine the diameter and wall thickness from the carotid and common femoral arteries. Carotid artery diameter did not change across 24 weeks, whilst femoral artery diameter stabilised after the rapid initial decrease during the first 3 weeks after the SCI. Carotid and femoral artery wall thickness showed no change during the first few weeks, but increased both between 6 and 24 weeks (P < 0.05). In conclusion, SCI leads to a rapid and localised decrease in conduit artery diameter which is isolated to the denervated and paralyzed region, whilst wall thickness gradually increases both above and below the lesion. This distinct time course of change in conduit arterial diameter and wall thickness suggests that distinct mechanisms may contribute to these adaptations.

Repeated increases in blood flow, independent of exercise, enhance conduit artery vasodilator function in humans.

This study aimed to determine the importance of repeated increases in blood flow to conduit artery adaptation, using an exercise-independent repeated episodic stimulus. Recent studies suggest that exercise training improves vasodilator function of conduit arteries via shear stress-mediated mechanisms. However, exercise is a complex stimulus that may induce shear-independent adaptations. Nine healthy men immersed their forearms in water at 42°C for three 30-min sessions/wk across 8 wk. During each session, a pneumatic pressure cuff was inflated around one forearm to unilaterally modulate heating-induced increases in shear. Forearm heating was associated with an increase in brachial artery blood flow (P<0.001) and shear rate (P<0.001) in the uncuffed forearm; this response was attenuated in the cuffed limb (P<0.005). Repeated episodic exposure to bilateral heating induced an increase in endothelium-dependent vasodilation in response to 5-min ischemic (P<0.05) and ischemic handgrip exercise (P<0.005) stimuli in the uncuffed forearm, whereas the 8-wk heating intervention did not influence dilation to either stimulus in the cuffed limb. Endothelium-independent glyceryl trinitrate responses were not altered in either limb. Repeated heating increases blood flow to levels that enhance endothelium-mediated vasodilator function in humans. These findings reinforce the importance of the direct impacts of shear stress on the vascular endothelium in humans.

Exercise-mediated changes in conduit artery wall thickness in humans: role of shear stress.

Episodic increases in shear stress have been proposed as a mechanism that induces training-induced adaptation in arterial wall remodeling in humans. To address this hypothesis in humans, we examined bilateral brachial artery wall thickness using high-resolution ultrasound in healthy men across an 8-wk period of bilateral handgrip training. Unilaterally, shear rate was attenuated by cuff inflation around the forearm to 60 mmHg. Grip strength, forearm volume, and girth improved similarly between the limbs. Acute bouts of handgrip exercise increased shear rate (P < 0.005) in the noncuffed limb, whereas cuff inflation successfully decreased exercise-induced increases in shear. Brachial blood pressure responses similarly increased during exercise in both the cuffed and noncuffed limbs. Handgrip training had no effect on baseline brachial artery diameter, blood flow, or shear rate but significantly decreased brachial artery wall thickness after 6 and 8 wk (ANOVA, P < 0.001) and wall-to-lumen ratio after week 8 (ANOVA, P = 0.005). The magnitude of decrease in brachial artery wall thickness and wall-to-lumen ratio after exercise training was similar in the noncuffed and cuffed arms. These results suggest that exercise-induced changes in shear rate are not obligatory for arterial wall remodeling during a period of 8 wk of exercise training in healthy humans.

Exercise and vascular adaptation in asymptomatic humans.

Beneficial effects of exercise training on the vasculature have been consistently reported in subjects with cardiovascular risk factors or disease, whereas studies in apparently healthy subjects have been less uniform. In this review, we examine evidence pertaining to the impact of exercise training on conduit and resistance vessel function and structure in asymptomatic subjects. Studies of arterial function in vivo have mainly focused on the endothelial nitric oxide dilator system, which has generally been shown to improve following training. Some evidence suggests that the magnitude of benefit depends upon the intensity or volume of training and the relative impact of exercise on upregulation of dilator pathways versus effects of inflammation and/or oxidation. Favourable effects of training on autonomic balance, baroreflex function and brainstem modulation of sympathetic control have been reported, but there is also evidence that basal vasoconstrictor tone increases as a result of training such that improvements in intrinsic vasodilator function and arterial remodelling are counterbalanced at rest. Studies of compliance suggest increases in both the arterial and the venous sides of the circulation, particularly in older subjects. In terms of mechanisms, shear stress appears to be a key signal to improvement in vascular function, whilst increases in pulse pressure and associated haemodynamics during bouts of exercise may transduce vascular adaptation, even in vascular beds which are distant from the active muscle. Different exercise modalities are associated with idiosyncratic patterns of blood flow and shear stress, and this may have some impact on the magnitude of exercise training effects on arterial function and remodelling. Other studies support the theory that that there may be different time course effects of training on specific vasodilator and constrictor pathways. A new era of understanding of the direct impacts of exercise and training on the vasculature is evolving, and future studies will benefit greatly from technological advances which allow direct characterization of arterial function and structure.

Distinguishing factors that influence attendance and behaviour change in family-based treatment of childhood obesity: A qualitative study.

OBJECTIVES: For the effective treatment of childhood obesity, intervention attendance and behaviour change at home are both important. The purpose of this study was to qualitatively explore influences on attendance and behaviour change during a family-based intervention to treat childhood obesity in the North West of England (Getting Our Active Lifestyles Started (GOALS)). DESIGN: Focus groups with children and parents/carers as part of a broader mixed-methods evaluation. METHODS: Eighteen focus groups were conducted with children (n = 39, 19 boys) and parents/carers (n = 34, 5 male) to explore their experiences of GOALS after 6 weeks of attendance (/18 weeks). Data were analysed thematically to identify influences on attendance and behaviour change. RESULTS: Initial attendance came about through targeted referral (from health care professionals and letters in school) and was influenced by motivations for a brighter future. Once at GOALS, it was the fun, non-judgemental healthy lifestyle approach that encouraged continued attendance. Factors that facilitated behaviour change included participatory learning as a family, being accountable and gradual realistic goal setting, whilst challenges focussed on fears about the intervention ending and a lack of support from non-attending significant others. CONCLUSIONS: Factors that influence attendance and behaviour change are distinct and may be important at different stages of the family's change process. Practitioners are encouraged to tailor strategies to support both attendance and behaviour change, with a focus on whole family participation within and outside the intervention.

Corrigendum: Cerebral Hemodynamic and Neurotrophic Factor Responses Are Dependent on the Type of Exercise.

[This corrects the article DOI: 10.3389/fphys.2020.609935.].

Obligatory role of hyperaemia and shear stress in microvascular adaptation to repeated heating in humans.

The endothelium, a single layer of cells lining the entire circulatory system, plays a key role in maintaining vascular health. Endothelial dysfunction independently predicts cardiovascular events and improvement in endothelial function is associated with decreased vascular risk. Previous studies have suggested that exercise training improves endothelial function in macrovessels, a benefit mediated via repeated episodic increases in shear stress. However, less is known of the effects of shear stress modulation in microvessels. In the present study we examined the hypothesis that repeated skin heating improves cutaneous microvascular vasodilator function via a shear stress-dependent mechanism. We recruited 10 recreationally active males who underwent bilateral forearm immersion in warm water (42 degrees C), 3 times per week for 30 min. During these immersion sessions, shear stress was manipulated in one arm by inflating a pneumatic cuff to 100 mmHg, whilst the other arm remained uncuffed. Vasodilatation to local heating, a NO-dependent response assessed using laser Doppler, improved across the 8 week intervention period in the uncuffed arm (cutaneous vascular conductance week 0 vs. week 4 at 41 degrees C: 1.37 +/- 0.45 vs. 2.0 +/- 0.91 units, P = 0.04; 42 degrees C: 2.06 +/- 0.45 vs. 2.68 +/- 0.83 units; P = 0.04), whereas no significant changes were evident in the cuffed arm. We conclude that increased blood flow, and the likely attendant increase in shear stress, is a key physiological stimulus for enhancing microvascular vasodilator function in humans.

Impact of catheter insertion using the radial approach on vasodilatation in humans.

The aim of this study was to determine the impact of catheter sheath insertion, a model of endothelium disruption in humans, on the conventional FMD (flow-mediated dilatation) response in vivo. Seventeen subjects undergoing transradial catheterization were recruited and assessed prior to, the day after, and 3-4 months postcatheterization. The catheter sheath's external diameter was 2.7 mm, and the average preprocedure internal radial artery diameter was 2.8 mm, indicating a high likelihood of endothelial denudation as a consequence of sheath placement. Radial artery flow-mediated and endothelium-derived NO (nitric oxide)-dependent function (FMD) was assessed within the region of sheath placement (sheath site) and also above the sheath (catheter site). GTN (glyceryl trinitrate) endothelium-independent NO-mediated function was also assessed distally. Measurements were made in both arms at all time points; the non-catheterized arm provided an internal control. Neither sheath (4.5+/-0.9%) nor catheter (4.4+/-0.9%) insertion abolished FMD, although both significantly decreased FMD from preintervention levels (9.0+/-0.8% sheath segment; 8.4+/-0.8% catheter segment; P<0.05). The impact of sheath and catheter placement on FMD was no longer evident after approximately 3 months recovery (8.0+/-1.5 and 8.1+/-1.7%, sheath and catheter, respectively). GTN responses also decreased from 14.8+/-1.7 to 7.9+/-1.0% (P<0.05) as a result of sheath placement, but values returned to baseline at approximately 3 months (13.0+/-1.8%). These results suggest that the presence of an intact, functional endothelial layer and consequent NO release may not be obligatory for some component of the FMD response. This raises the possibility of an endothelium-independent contribution to the flow-induced vasodilatation in humans.