Michael Nyberg

Novo Nordisk · Vascular Biology

Background Drug target Mendelian randomization describes the use of genetic variants as instrumental variables for studying the effects of pharmacological agents. The paradigm can be used to inform on all aspects of drug development and has become increasingly popular over the last decade, particularly given the time- and cost-efficiency with which...

Intro: Vascular smooth muscle cell (VSMC) proliferation following endovascular interventions leads to restenosis, treated with drug-eluting stents. However, current drugs completely abolish vascular healing, cause thrombosis and clinical events. PCSK6 is a key protease in vascular remodeling and VSMCs activation upon vessel injury, via regulation o...

The significant morbidity and premature mortality of type 2 diabetes mellitus (T2DM) is largely associated with its cardiovascular consequences. Focus has long been on the arterial atheromatosis of DM giving rise to early stroke and myocardial infarctions, whereas less attention has been given to its non-ischemic cardiovascular consequences. Irresp...

Atherosclerosis is a pervasive contributor to cardiovascular diseases including ischemic heart disease and stroke. Despite the advance and success of effective lipid lowering-therapies and hypertensive agents, the residual risk of an atherosclerotic event remains high and improving disease understanding and development of novel therapeutic strategi...

The role of C‐type natriuretic peptide (CNP) in the regulation of cardiac function in humans remains to be established as previous investigations have been confined to animal model systems. Here, we used well‐characterized engineered cardiac tissues (ECTs) generated from human stem cell‐derived cardiomyocytes and fibroblasts to study the acute effe...

Background C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework. Methods Instrumental variables mimickin...

The authors determined the effect of the GLP-1 receptor agonist liraglutide on endothelial surface expression of vascular cell adhesion molecule (VCAM)-1 in murine apolipoprotein E knockout atherosclerosis. Contrast-enhanced ultrasound molecular imaging using microbubbles targeted to VCAM-1 and control microbubbles showed a 3-fold increase in endot...

Measurement of natriuretic peptides (NPs) has proven its clinical value as biomarker, especially in the context of heart failure (HF). In contrast, a state partial NP deficiency appears integral to several conditions in which lower NP concentrations in plasma presage overt cardiometabolic disease. Here, obesity and type 2 diabetes have attracted co...

Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-7, MBTPS1, and PCSK9. Apart from PCSK9, little is known about PCSKs in cardiovascular disease. Here, we aimed to investigate the expression landscape and druggability potential of the entire PCSK family for CVD. We applied an integrative approach, c...

Skeletal muscle is one of the most dynamic metabolic organs as evidenced by increases in metabolic rate of >150-fold from rest to maximal contractile activity. Because of limited intracellular stores of ATP, activation of metabolic pathways is required to maintain the necessary rates of ATP re-synthesis during sustained contractions. During the ver...

Background and aims Randomized clinical studies have shown a reduction in cardiovascular outcomes with glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with the hypothesized mechanisms being an underlying effect on atherosclerosis. Here, we aimed to assess the pharmacological effects of semaglutide in an atheroprone murine model that re...

Patients with heart failure with preserved ejection fraction (HFpEF) and atherosclerosis-driven coronary artery disease (CAD) will have ongoing fibrotic remodeling both in the myocardium and in atherosclerotic plaques. However, the functional consequences of fibrosis differ for each location. Thus, cardiac fibrosis leads to myocardial stiffening, t...

Introduction: Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of 7 related proteases (PCSK1-7) and 2 distant ones (MBTPS1, PCSK9), with unexplored role in cardiovascular disease (CVD), apart from PCSK9 in lipid metabolism. Here, we aimed to investigate the expression landscape and therapeutic targeting potential of the entire PC...

Dietary nitrate supplementation has been shown to reduce pulmonary O2 uptake during submaximal exercise and enhance exercise performance. However, the effects of nitrate supplementation on local metabolic and haemodynamic regulation in contracting human skeletal muscle remain unclear. To address this, eight healthy young male sedentary subjects wer...

The influence of the menopausal transition, with a consequent loss of oestrogen, on capillary growth in response to exercise training remains unknown. In the present study, we evaluated the effect of a period of intense endurance training on skeletal muscle angiogenesis in late pre-menopausal and recently post-menopausal women with an age differenc...

Purpose: Skeletal muscle vascularization is important for tissue regeneration after injury and immobilization. We examined whether complete immobilization influences capillarization and oxygen delivery to the muscle and assessed the efficacy of rehabilitation by aerobic exercise training. Methods: Young healthy males had one leg immobilized for...

Complications of atherosclerosis are the leading cause of morbidity and mortality worldwide. Various genetically modified mouse models are used to investigate disease trajectory with classical histology, currently the preferred methodology to elucidate plaque composition. Here, we show the strength of light-sheet fluorescence microscopy combined wi...

Purpose of review: Despite the wide use of statins and other LDL-cholesterol (LDL-C)-lowering therapies, atherosclerotic cardiovascular disease remains an important cause of mortality and morbidity. Here, we discuss efficacy, side effects and convenience of current and future therapies inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK...

Background and aims Clinical interventions targeting nonlipid risk factors are needed given the high residual risk of atherothrombotic events despite effective control of dyslipidemia. Dickkopf-1 (DKK1) plays a lipid-independent role in vascular pathophysiology but its involvement in atherosclerosis development and its therapeutic attractiveness re...

The menopausal transition is associated with increased prevalence of hypertension, and in time postmenopausal women (PMW) will exhibit a cardiovascular disease risk-score similar to male counterparts. Hypertension is associated with vascular dysfunction, but whether hypertensive PMW have blunted nitric-oxide (NO)-mediated leg vasodilator responsive...

The menopausal transition is accompanied by changes in adipose tissue storage, leading to an android body composition associated with increased risk of type 2 diabetes and cardiovascular disease in post-menopausal women. Estrogens probably affect local adipose tissue depots differently. We investigated how menopausal status and exercise training in...

Essential hypertension is associated with impairments in vascular function and sympathetic nerve hyperactivity; however, the extent to which the lower limbs are affected remains unclear. We examined the leg vascular responsiveness to infusion of acetylcholine (ACh), sodium nitroprusside (SNP) and phenylephrine (PEP) in ten hypertensive men (HYP: ag...

Purpose: We examined whether two weeks of one-leg immobilization would impair leg microvascular function and to what extent a subsequent period of intense aerobic cycle training could restore function. Methods: Study participants were healthy young males (n=12; 20-24 years of age). Leg microvascular function was determined before the interventio...

Key points Increased insulin action is an important component of the health benefits of exercise, but its regulation is complex and not fully elucidated. Previous studies of insulin‐stimulated GLUT4 translocation to the skeletal muscle membrane found insufficient increases to explain the increases in glucose uptake. By determination of leg glucose...

The study examined the effect of 8 weeks of exercise training on ATP signalling in human skeletal muscle of 15 young (25±1 years) and 15 older (72±1 years) recreationally active male subjects. Before training, femoral venous plasma [ATP] was higher (P<0.05) during low‐intensity knee‐extensor exercise in the older than the young group. During modera...

Key points Training with blood flow restriction (BFR) is a well‐recognized strategy for promoting muscle hypertrophy and strength. However, its potential to enhance muscle function during sustained, intense exercise remains largely unexplored. In the present study, we report that interval training with BFR augments improvements in performance and r...

Background: We examined the influence of recent menopause and aerobic exercise training in women on myocardial perfusion, left ventricular (LV) dimension and function. Methods: Two groups (n=14 each) of healthy late pre- (50.2±2.1 years) and recent postmenopausal (54.2±2.8 years) women underwent cardiac magnetic resonance imaging (cMRI) at basel...

Aim: The aim was to determine the role of aging and exercise training on endothelial mechanosensor proteins and the hyperemic response to shear stress by passive leg movement. Methods: We examined the expression of mechanosensor proteins and vascular function in young (n = 14, 25 ± 3 years) and old (n = 14, 72 ± 5 years) healthy male subjects with...

Objective: The axis of apolipoprotein M (apoM) and sphingosine-1-phosphate (S1P) is of importance to plasma lipid levels, endothelial function, and development of atherosclerosis. Menopause is accompanied by dyslipidemia and an increased risk of atherosclerosis, which can be lowered by exercise training. The aim of this study was to explore if eff...

Detailed physiological phenotyping was hypothesized to have predictive value for Olympic distance cross-country mountain bike (XCO-MTB) performance. Additionally, mean (MPO) and peak power output (PPO) in 4 × 30 s all-out sprinting separated by 1 min was hypothesized as a simple measure with predictive value for XCO-MTB performance. Parameters indi...

Objective The relationship between skeletal muscle perfusion, interstitial glucose concentration and sarcolemmal permeability to glucose in exercise-induced increases in muscle insulin sensitivity is not well established. A single bout of exercise increases skeletal muscle insulin sensitivity through coordinated increases in insulin-stimulated micr...

Key points: Animal models have shown that beta2 -adrenoceptor stimulation increases protein synthesis and attenuates breakdown processes in skeletal muscle. Thus, the beta2 -adrenoceptor is a potential target in the treatment of disuse-, disease- and age-related muscle atrophy. In the present study, we show that a few days of oral treatment with t...

Background: The long term benefits of exercise on the cardiovascular status of a patient have been proven, however, their benefit/risk relationship with exercise intensity is unclear. Furthermore, many thromboembolic diseases such as myocardial infarction and ischaemic stroke are associated with profound catecholamine release. In this study we exp...

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 aim of this study was to investigate the levels of motivation associated with participation in floorball (indoor hockey) and spinning, and how levels of motivation predicted continuation. A sample of 66 middle-aged women participated in a 12-week intervention of either floorball or spinning. They filled out the Sport Motivation Scale in week 2...

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...

Background: The risk of atherothrombotic events increases after menopause. Regular physical activity has been shown to reduce platelet reactivity in younger women, but it is unknown how regular exercise affects platelet function after menopause. Objectives: To examine the effects of regular aerobic exercise in late pre- and recent postmenopausal...

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...

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...

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...

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...

Purpose: We tested the hypothesis that low-volume high-intensity swimming has a larger impact on insulin sensitivity and glucose control than high-volume low-intensity swimming in inactive premenopausal women with mild hypertension. Methods: Sixty-two untrained premenopausal women were randomised to an inactive control (n = 20; CON), a high-inte...

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...

Menopause is associated with a decline in vascular function; however, whether this is an effect of age and/or menopause and the mechanisms underlying this decline remains unclear. We examined the vascular response to femoral arterial infusion of vasoactive compounds in 20 pre‐and 17 recent postmenopausal women of similar age (49±2 vs. 53±2 years)....

Aging is associated with impaired blood flow regulation; however, the mechanisms underlying this impairment and to what extent a period of exercise training can improve the matching between O 2 delivery and utilization remain unclear. Eight young and 6 older (24 ± 1 vs. 74 ±2 years) healthy sedentary men participated in the study. We examined the v...

Purpose: The present study examined whether a period of additional speed endurance training would improve intense intermittent exercise performance in highly trained soccer players during the season and whether the training changed aerobic metabolism and the level of oxidative enzymes in type I and II muscle fibers. Methods: During the last nine...

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...

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...

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...

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...

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...

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...

New Findings What is the central question of this study? In the transition from rest to exercise, skeletal muscle blood flow, oxygen delivery and extraction of oxygen from the blood increase to accommodate the need for additional oxygen in the contracting fibres. To what extent skeletal muscle blood flow and oxygen delivery limit the rise in skelet...

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...

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...