Ylva Hellsten

• University of Copenhagen

Background Exercise in healthy individuals is associated with a hypercoagulable phase, leading to a temporary increase in clot mass and strength, which are controlled by an effective fibrinolytic system. Conversely, people with cardiovascular diseases often have a reduced fibrinolytic pathway, increased clot mass and abnormal clot contraction, resu...

The present study examined and compared the impact of exercise training on redox and molecular properties of human microvascular endothelial cells derived from skeletal muscle biopsies from sedentary recent (RPF, ≤ 5 years as postmenopausal) and late (LPF, ≥ 10 years as postmenopausal) postmenopausal females. Resting skeletal muscle biopsies were o...

Introduction Older individuals and, in particular, individuals at risk of recurrent stroke, may be susceptible to thrombosis when participating in exercise, however, this aspect has not been well investigated. Methods Clot microstructure and conventional markers of thrombotic risk were determined in twenty lacunar stroke patients and fifteen healt...

Background: This study tested the hypothesis that training reduces resting sympathetic activity and improves baroreflex control in both hypertensive and normotensive men but reduces blood pressure only in hypertensive men. Methods: Middle-aged/older un-medicated stage-1 hypertensive males (mean age 55±3 yrs; n=13) and normotensive controls (mean...

Key points The risk of cardiovascular disease and associated skeletal muscle microvascular rarefaction is enhanced in women after menopause, yet knowledge about the angiogenic potential in ageing women is generally sparse. Aged healthy and sedentary women were found to present a markedly impaired capacity for proliferation of skeletal muscle derive...

Objective: The effect of insulin on blood flow distribution within muscle microvasculature, has been suggested to be important for glucose metabolism. However, the 'capillary recruitment' hypothesis is still controversial and relies on studies using indirect contrast-enhanced ultrasound (CEU) methods. Methods: We studied how hyperinsulinaemia ef...

As women enter menopause at mid‐life, oestrogen production ceases and its many beneficial effects on cardiovascular health are lost whereby the age‐related risk of cardiovascular disease is accelerated. Oestrogen acts via oestrogen receptors and can activate the oestrogen response element leading to upregulation of a number of proteins of importanc...

A number of mechanisms govern the rapid and precise changes in blood flow which occur in skeletal muscle with alterations in metabolic demand. Such mechanisms include sympathetic activity, functional sympatholysis, conducted vasodilation, flow mediated dilation, and compounds which stimulate formation of endothelium derived vasodilators. Compounds...

Since the first measurements of limb blood flow at rest and during nerve stimulation were conducted in the late 1800s, a number of methods have been developed for the determination of limb and skeletal muscle blood flow in humans. The methods, which have been applied in the study of aspects such as blood flow regulation, oxygen uptake and metabolis...

Limb muscle dysfunction in patients with COPD may be associated with local muscle and/or systemic inflammation, and therefore, we investigated whether exercise training altered markers of inflammation and oxidative stress. We obtained vastus lateralis muscle biopsies and venous blood samples from patients with COPD (n=30) before and after 8 weeks o...

Aging is associated with slower skeletal muscle O2 uptake (VO2) kinetics; however, the mechanisms underlying this effect of age are unclear. Also, the effects of exercise training in elderly on the initial vascular and metabolic response to exercise remain to be elucidated. We measured leg hemodynamics and oxidative metabolism in the transition fro...

The cover image, by Y. Hellsten and L. Gliemann, is based on the Review Limb vascular function in women—Effects of female sex hormones and physical activity, DOI: 10.1002/tsm2.3.

The mechanisms that regulate bone blood flow (BBF) in humans are largely unknown. Animal studies suggest that nitric oxide (NO) could be involved and in the present study we investigated the effects of inhibition of nitric oxide synthase (NOS) alone and in combination with inhibition of cyclooxygenase (COX) enzyme, thus prostaglandin (PG) synthesis...

Aim: To explore how exercise-induced improvements in vascular and platelet function affect the efficacy of dual anti-platelet therapy, in a cross-sectional study of men with different physical activity level (training status). Methods: 42 healthy, normal-weight, middle-aged men were divided into 3 groups; untrained, moderately- and well-trained....

The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction during exercise, termed functional sympatholysis, can be improved by exercise training. However, to what extent age affects functional sympatholysis is unclear. Thus, the current study examined the effect of 8 weeks of high-intensity exercise training on α-adrenerg...

Coordination of vascular smooth muscle cell tone in resistance arteries plays an essential role in the regulation of peripheral resistance and overall blood pressure. Recent observations in animals have provided evidence for a coupling between adrenoceptors and Panx1 (pannexin-1) channels in the regulation of sympathetic nervous control of peripher...

Physical activity has the potential to offset age-related impairments in the regulation of blood flow and O 2 delivery to the exercising muscles; however, the mechanisms underlying this effect of physical activity remain poorly understood. The present study examined the role of cGMP in training-induced adaptations in the regulation of skeletal musc...

PGC-1α has been suggested to regulate exercise training-induced metabolic adaptations and autophagy in skeletal muscle. The factors regulating PGC-1α are however not fully resolved. The aim was to investigate the impact of β-adrenergic signaling in PGC-1α mediated metabolic adaptations in skeletal muscle with exercise training. Muscle was obtained...

Objective: To investigate peripheral insulin sensitivity and skeletal muscle glucose metabolism in premenopausal and postmenopausal women, and evaluate whether exercise training benefits are maintained after menopause. Methods: Sedentary, healthy, normal-weight, late premenopausal (n = 21), and early postmenopausal (n = 20) women were included i...

Background We examined the role of menopause on cardiac dimensions and function and assessed the efficacy of exercise training before and after menopause. Methods and Results Two groups of healthy premenopausal (n=36, 49.4±0.3 years) and postmenopausal (n=37, 53.5±0.5 years) women with no history of cardiovascular disease and with a mean age diffe...

Skeletal muscle blood flow is regulated to match the oxygen demand and dysregulation could contribute to exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). We measured leg hemodynamics and metabolites from vasoactive compounds in muscle interstitial fluid and plasma at rest, during one-legged knee-extensor exercise,...

Key points: Mechanotransduction in endothelial cells is a central mechanism in the regulation of vascular tone and vascular remodelling Mechanotransduction and vascular function may be affected by high sugar levels in plasma because of a resulting increase in oxidative stress and increased levels of advanced glycation end-products (AGE). In health...

Key points: Exercise training effectively improves vascular and skeletal muscle function; however, these effects of training may be blunted in postmenopausal women as a result of the loss of oestrogens. Accordingly, the capacity to deliver oxygen to the active muscles may also be impaired in postmenopausal women. In both premenopausal and recent p...

Aim: To investigate the effect of elevated basal shear stress on angiogenesis in humans, and the role of enhanced skeletal muscle capillarisation on blood flow and O2 extraction. Methods: Limb haemodynamics and O2 extraction was measured at rest and during one-leg knee-extensor exercise (12 and 24W) in 10 healthy untrained young men before and a...

Background: Menopause is associated with increased risk of cardiovascular disease and the causal factors have been proposed to be the loss of estrogen and the subsequent alterations of the hormonal milieu. However, which factors contribute to the deterioration of cardiometabolic health in postmenopausal women is debated as the menopausal transitio...

Introduction Exercise is an important countermeasure to limb muscle dysfunction in COPD. The two major training modalities in COPD rehabilitation, endurance training (ET) and resistance training (RT), may both be efficient in improving muscle strength, exercise capacity, and health-related quality of life, but the effects on quadriceps muscle chara...

The postmenopausal phase is associated with an accelerated rate of rise in the prevalence of vascular dysfunction and hypertension; however, the mechanisms underlying these adverse vascular changes and whether exercise training can reverse the decline in vascular function remains unclear. We examined the function of the vascular prostanoid system i...

Introduction: The purposes of the present study was to examine the effect of intermittent exercise training on musculoskeletal and metabolic health in postmenopausal (PM) and premenopausal (PRM) women and, furthermore, to evaluate whether the adaptations can be maintained with a reduced training frequency. Methods: Eighteen PM (51 ± 1 yr, mean ±...

Cardiovascular disease is a leading cause of death in the western world with aging being one of the strongest predictors of cardiovascular events. Aging is associated with impaired vascular function due to endothelial dysfunction and altered redox balance, partly caused by an increased formation of reactive oxygen species combined with a reduction...

Intermittent claudication (IC) is the most commonly reported symptom of peripheral arterial disease (PAD). Impaired limb blood flow is a major casual factor of lower exercise tolerance in PAD, but cannot entirely explain it. We hypothesized that IC is associated with structural changes of the capillary-mitochondria interface that could contribute t...

Aerobic exercise training leads to cardiovascular changes that markedly increase aerobic power and lead to improved endurance performance. The functionally most important adaptation is the improvement in maximal cardiac output which is the result of an enlargement in cardiac dimension, improved contractility, and an increase in blood volume, allowi...

Regulation of skeletal muscle blood flow is a complex process, which involves an integration of multiple mechanisms and a number of vasoactive compounds. Overall, muscle blood flow is regulated through a balance between vasoconstrictor and vasodilator signals. In a healthy cardiovascular system, the increase in muscle blood flow required for oxygen...

Background: Peripheral arterial disease (PAD) is characterised by impaired leg blood flow, which contributes to claudication and reduced exercise capacity. This study investigated to what extent vasoactive enzymes might contribute to altered blood flow in PAD (Fontaine stage II). Methods: We compared femoral artery blood flow during reactive hyp...

The role of capillaries is to serve as the interface for delivery of oxygen and removal of metabolites to/from tissues. During the past decade there has been a proliferation of studies that have advanced our understanding of angiogenesis demonstrating tissue capillary supply is under strict control during health, but poorly controlled in disease -...

Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we examined whether this effe...

Transfection of rat skeletal muscle in vivo is a widely used research model. However, gene electrotransfer protocols have been developed for mice and yield variable results in rats. We investigated whether changes in hyaluronidase pre-treatment and plasmid DNA delivery can improve transfection efficiency in rat skeletal muscle. We found that pre-tr...

Aging is associated with progressive loss of cardiovascular and skeletal muscle function. The impairment in physical capacity with advancing age could be related to an insufficient peripheral O2 delivery to the exercising muscles. Furthermore, the mechanisms underlying an impaired blood flow regulation remain unresolved. Cyclic guanosine monophosph...

Exercise is a potent stimulator of angiogenesis in skeletal muscle; a few weeks of aerobic exercise training can increase capillarization by 10–30% in sedentary individuals, and after years of progressive endurance training capillarization can reach levels that are over 200% higher in the trained than in untrained skeletal muscle. The present Conne...

The ability to sustain a given absolute submaximal workload declines with advancing age likely due to a lower level of blood flow and O2 delivery to the exercising muscles. Given that physical inactivity mimics many of the physiological changes associated with ageing, separating the physiological consequences of ageing and physical inactivity can b...

BACKGROUND:The aim was to investigate the molecular mechanisms behind exercise training-induced improvements in glucose regulation in aged subjects. METHODS:Twelve elderly male subjects completed 8 weeks of exercise training. Before and after the training period, the subjects completed an oral glucose tolerance test (OGTT) and a muscle biopsy was...

AimThe aim was to elucidate whether essential hypertension is associated with altered capillary morphology and density and to what extend exercise training can normalize these parameters.Methods To investigate angiogenesis and capillary morphology in essential hypertension, muscle biopsies were obtained from m. vastus lateralis in essential hyperte...

Aim: The aim was to elucidate whether essential hypertension is associated with altered capillary morphology and density and to what extent exercise training can normalize these parameters. Methods: To investigate angiogenesis and capillary morphology in essential hypertension, muscle biopsies were obtained from m. vastus lateralis in subjects with...

Background : After menopause women experience a markedly increased risk of cardiovascular events due to the loss of estrogen. As estrogen replacement is associated with negative side effects, a more attractive alternative to help maintain a good cardiovascular and metabolic health status may be regular physical activity. In this ongoing study, our...

Background : After menopause women experience a markedly increased risk of cardiovascular events due to the loss of estrogen. As estrogen replacement is associated with negative side effects, a more attractive alternative to help maintain a good cardiovascular and metabolic health status may be regular physical activity. In this ongoing study, our...

In human skeletal muscle, the capillary net readily adapts according to the level of muscular activity to allow for optimal diffusion conditions for oxygen from the blood to the muscle. Animal studies have demonstrated that stimulation of capillary growth in skeletal muscle can occur either by mechanical or by chemical signalling. Mechanical signal...

The death of Bengt Saltin is an enormous loss. With his exceptional contribution at so many levels, he has, like no one else in the world, been at the forefront of the development of exercise and sports physiology, primarily within research but also in education.

The present study examined the effect of training by the 10-20-30 concept on performance, blood pressure (BP), and skeletal muscle angiogenesis as well as the feasibility of completing high-intensity interval training in local running communities. One hundred sixty recreational runners were divided into either a control group (CON; n = 28), or a 10...

Increased skeletal muscle capillarization is associated with improved glucose tolerance and insulin sensitivity. However, a possible causal relationship has not previously been identified. We therefore investigated whether increased skeletal muscle capillarization increases insulin sensitivity. Skeletal muscle specific angiogenesis was induced by a...

Aim: The polyphenol resveratrol has in animal studies been shown to influence several pathways of importance for angiogenesis in skeletal muscle. The aim was to examine the angiogenic effect of resveratrol supplementation with parallel exercise training in aged men. Methods: Forty-three healthy physically inactive aged men (65±1 years) were divided...

Aims: To determine the role played by adenosine, ATP and chemoreflex activation on the regulation of vascular conductance in chronic hypoxia. Methods: The vascular conductance response to low and high doses of adenosine and ATP was assessed in ten healthy men. Vasodilators were infused into the femoral artery at sea level and then after 8-12 day...

Reactive oxygen species (ROS) are important signaling molecules with regulatory functions, and in young and adult organisms, the formation of ROS is increased during skeletal muscle contractions. However, ROS can be deleterious to cells when not sufficiently counterbalanced by the antioxidant system. Aging is associated with accumulation of oxidati...

Key points Essential hypertension is linked to an increased sympathetic vasoconstrictor activity and reduced tissue perfusion. Exercise training can improve the ability to override sympathetic vasoconstrictor activity. Here we show that 8 weeks of exercise training reduces the vasoconstrictor response to sympathetic nerve activity (induced by tyram...

Key points Ageing is associated with lifestyle‐related metabolic diseases, and exercise training has been suggested to counteract such metabolic deteriorations. The natural antioxidant resveratrol has been reported to exert ‘exercise‐like’ health beneficial metabolic and anti‐inflammatory effects in rodents, but little is known about the metabolic...

Menopause is associated with an accelerated decline in vascular function, however, whether this is an effect of age and/or menopause and how exercise training may affect this decline remains unclear. We examined a range of molecular measures related to vascular function in matched pre- and post-menopausal women before and after 12 weeks of exercise...

In skeletal muscle, growth of capillaries is an important adaptation to exercise training that secures adequate diffusion capacity for oxygen and nutrients even at high intensity exercise when increases in muscle blood flow are profound. Mechanical forces present during muscle activity, such as shear stress and passive stretch, lead to cellular sig...

Peripheral arterial disease (PAD) is caused by atherosclerosis and is associated with microcirculatory impairments in skeletal muscle. The present study evaluated the angiogenic response to exercise and passive movement in skeletal muscle of PAD patients compared to healthy control subjects. Twenty-one PAD patients and 17 aged controls were randoml...

Key points In rodents, resveratrol has been shown to enhance training‐induced changes in cardiovascular function, exercise performance and the retardation of atherosclerosis. We examined the effect of 8 weeks of exercise training with and without concomitant resveratrol supplementation in aged men. Exercise training potently improved blood pressure...

The present study examined if a marked reduction in oxygen delivery, unlike findings with moderate intensity exercise, would slow leg oxygen uptake (VO2) kinetics during intense exercise (86±3% of incremental test peak power). Seven healthy males (26±1 years, mean±SEM) performed one-legged knee-extensor exercise (60±3 W) for 4 min in a control sett...

The subcellular distribution and secretion of vascular endothelial growth factor (VEGF) was examined in skeletal muscle of healthy humans. Skeletal muscle biopsies were obtained from m.v. lateralis before and after a 2 h bout of cycling exercise. VEGF localization was conducted on preparations of teased muscle fibers by transmission electron micros...

Subjects with a low birth weight (LBW) display increased risk of developing type 2 diabetes (T2D). We hypothesized that this is associated with defects in muscle adaptations following acute and regular physical activity, evident by impairments in the exercise-induced activation of AMPK signaling. We investigated 21 LBW and 21 normal birth weight (N...

Endurance training lowers heart rate and blood pressure responses to exercise, but the mechanisms and consequences remain unclear. To determine the role of skeletal muscle for the cardioventilatory response to exercise, 8 healthy young men were studied before and after 5 weeks of 1-legged knee-extensor training and 2 weeks of deconditioning of the...

Endothelin-1 has potent constrictor and proliferative activity in vascular smooth muscle, and essential hypertension and aging are associated with increased endothelin-1-mediated vasoconstrictor tone. The aim of this study was to investigate the effect of physical activity, hypertension and age on endothelin-1 levels in plasma and skeletal muscle a...

During exercise, oxygen delivery to skeletal muscle is elevated to meet the increased oxygen demand. The increase in blood flow to skeletal muscle is achieved by vasodilators formed locally in the muscle tissue, either on the intraluminal or the extraluminal side of the blood vessels. A number of vasodilators have been shown to bring about this inc...

New findings What is the central question of this study? Does intense intermittent exercise provide a sufficient angiogenic stimulus to induce capillary growth in skeletal muscle conditioned by moderate intensity exercise training? What is the main finding and its importance? We show that higher levels of shear stress and metabolism associated with...

: This study examined vascular function and the adenosine system in skeletal muscle of patients diagnosed with essential hypertension (n = 10) and of normotensive (n = 11) patients, before and after aerobic training. : Before and after 8 weeks of aerobic training, the patients completed experiments in which leg blood flow was determined during infu...

Key points Ageing has been proposed to be associated with increased levels of reactive oxygen species (ROS) that scavenge nitric oxide (NO), thereby decreasing the bioavailability of this potent vasodilator. Here we show that NO bioavailability is compromised in the systemic circulation and in skeletal muscle of sedentary older humans as evidenced...

This investigation examined the influence of the number of repetitions per set on power output and muscle metabolism during leg press exercise. Six trained men (age 34 ± 6 yr) randomly performed either 5 sets of 10 repetitions (10REP), or 10 sets of 5 repetitions (5REP) of bilateral leg press exercise, with the same initial load and rest intervals...

Key points Passive leg movement is associated with a ∼3‐fold increase in blood flow to the leg, but the underlying mechanisms remain unknown. Passive leg movement increased venous levels of metabolites of nitric oxide (NO) in young subjects, whereas they remained unaltered in the muscle interstitial space. Inhibition of NO synthesis lowered the vas...

Abstract  The regulation of blood flow to skeletal muscle involves a complex interaction between several locally formed vasodilators that are produced both in the skeletal muscle interstitium and intravascularly. The gas nitric oxide (NO) and the purines ATP and adenosine, are potent vasodilators that are formed by multiple cell types and released...

We thank Tsikas et al1 for the interest in our findings. An underlying concern of Tsikas et al1 is our use of an immunoassay for the determination of prostaglandins,2 a method that most studies on prostaglandins in the literature have used. Their point is that our prostaglandin values in muscle microdialysate are too high. Our measured levels are v...

During exercise, contracting muscles can override sympathetic vasoconstrictor activity (functional sympatholysis). ATP and adenosine have been proposed to play a role in skeletal muscle blood flow regulation. However, little is known about the role of muscle training status on functional sympatholysis and ATP- and adenosine-induced vasodilation. Ei...

Key points Nitric oxide and prostanoids are substances that dilate the blood vessels. We examined the role of these vasodilators in the regulation of blood flow to contracting muscle and systemic blood pressure before and after a training intervention in subjects with essential hypertension and in healthy controls. We show that blood flow to the e...

This study examined the effect of acute exercise and 4 weeks of aerobic training on skeletal muscle gene and protein expression of pro- and anti-angiogenic factors in 14 young male subjects. Training consisted of 60 min of cycling (∼60% of ), 3 times/week. Biopsies were obtained from vastus lateralis muscle before and after training. Muscle interst...

The effects of physical training on the formation of vasodilating and vasoconstricting compounds, as well as on related proteins important for vascular function, were examined in skeletal muscle of individuals with essential hypertension (n=10). Muscle microdialysis samples were obtained from subjects with hypertension before and after 16 weeks of...

The aim of the present study was to determine the effect of nitric oxide and prostanoids on microcirculation and oxygen uptake, specifically in the active skeletal muscle by use of positron emission tomography (PET). Healthy males performed three 5-min bouts of light knee-extensor exercise. Skeletal muscle blood flow and oxygen uptake were measured...

The hypothesis investigated whether exercise performance over a broad range of intensities is determined by specific skeletal muscle characteristics. Seven subjects performed 8-10 exhaustive cycle trials at different workloads, ranging from 150 to 700 W (150 min to 20 s). No relationships between the performance times at high and low workloads were...

Intraluminal ATP could play an important role in the local regulation of skeletal muscle blood flow, but the stimuli that cause ATP release and the levels of plasma ATP in vessels supplying and draining human skeletal muscle remain unclear. To gain insight into the mechanisms by which ATP is released into plasma, we measured plasma [ATP] with the i...

One major unresolved issue in muscle blood flow regulation is that of the role of circulating versus interstitial vasodilatory compounds. The present study determined adenosine-induced formation of NO and prostacyclin in the human muscle interstitium versus in femoral venous plasma to elucidate the interaction and importance of these vasodilators i...

Information about anaerobic energy production and mechanical efficiency that occurs over time during short-lasting maximal exercise is scarce and controversial. Bilateral leg press is an interesting muscle contraction model to estimate anaerobic energy production and mechanical efficiency during maximal exercise because it largely differs from the...

The role of adenosine and contraction for secretion of vascular endothelial growth factor (VEGF) in skeletal muscle was investigated in human subjects and rat primary skeletal muscle cells. Microdialysis probes were inserted in the thigh muscle of seven male subjects, and dialysate was collected at rest, during infusion of adenosine, and during kne...

The effect of low blood flow at onset of moderate-intensity exercise on the rate of rise in muscle oxygen uptake was examined. Seven male subjects performed a 3.5-min one-legged knee-extensor exercise bout (24 +/- 1 W, mean +/- SD) without (Con) and with (double blockade; DB) arterial infusion of inhibitors of nitric oxide synthase (N(G)-monomethyl...

Vascular endothelial growth factor (VEGF) protein and capillarization were determined in muscle vastus lateralis biopsy samples in individuals with essential hypertension (n = 10) and normotensive controls (n = 10). The hypertensive individuals performed exercise training for 16 weeks. Muscle samples as well as muscle microdialysis fluid samples we...

To investigate if exercise intensity and Ca(2+) signalling regulate Na(+),K(+) pump mRNA expression in skeletal muscle. The importance of exercise intensity was evaluated by having trained and untrained humans perform intense intermittent and prolonged exercise. The importance of Ca(2+) signalling was investigated by electrical stimulation of rat s...

Adenosine is a widely used pharmacological agent to induce a "high-flow" control condition to study the mechanisms of exercise hyperemia, but it is not known how well an adenosine infusion depicts exercise-induced hyperemia, especially in terms of blood flow distribution at the capillary level in human muscle. Additionally, it remains to be determi...

ATP has been proposed to play multiple roles in local skeletal muscle blood flow regulation by inducing vasodilation and modulating sympathetic vasoconstrictor activity, but the mechanisms remain unclear. Here we evaluated the effects of arterial ATP infusion and exercise on leg muscle interstitial ATP and norepinephrine (NE) concentrations to gain...

Extracellular nucleotides and nucleosides are involved in regulation of skeletal muscle blood flow. Diabetes induces cardiovascular dysregulation, but the extent to which the vasodilatatory capacity of nucleotides and nucleosides is affected in type 2 diabetes is unknown. The present study investigated 1) the vasodilatatory effect of ATP, uridine-t...

Adenosine can induce vasodilation in skeletal muscle, but to what extent adenosine exerts its effect via formation of other vasodilators and whether there is redundancy between adenosine and other vasodilators remain unclear. We tested the hypothesis that adenosine, prostaglandins, and NO act in synergy to regulate skeletal muscle hyperemia by dete...