The vascular endothelium is a single layer of cells that lines the interior surface of our blood vessels. The endothelium plays a key role in vasoprotection and vasoregulation and its proper function is therefore essential to the maintenance of vascular health. The endothelial cells respond to the frictional force (shear stress (SS)) that occurs with an increase in blood flow. As a response, vasoactive substances are released, causing the artery to dilate, this is termed flow-mediated dilation (FMD). Endothelial cell function can be assessed by measuring the vasodilatory response to an increase in SS. Currently however, our ability to interpret the results of FMD assessment in order to make accurate judgements regarding arterial health is hindered by an incomplete understanding of the “dose-response” relationship between SS and FMD. The dose-response relationship is characterized by 1) the SS stimulus required to elicit an FMD response (threshold), 2) the magnitude of dilation for a given increase in SS (the slope of the SS-FMD relationship), and 3) the point at which further increases in SS no longer elicit dilation (the ceiling). The primary purpose of the current study was to characterize the magnitude and day-to-day variability of the parameters described above. N=20 males (mean 22-years). Brachial artery diameter (BAD) and blood velocity (BV) were assessed with echo and Doppler ultrasound. SS was estimated as shear rate (SR=BV/BAD). Subjects performed 2 incremental handgrip exercise trials on two separate visits (V1 and V2). CV=co-efficient of variation. The SS-FMD relationship was characterized by a shallow slope followed by an inflection point (threshold (T1)) and a steeper slope (pre vs. post T1 slope p=0.002). There was no difference between V1 vs. V2 in the SR-FMD slope or threshold (p>0.05), but there was considerable within-subject variability in the SR-FMD parameters: pre-T1 slope CV = 47.0 ± 33.1%; post-T1 slope CV = 55.3 ± 40.7%; T1 CV = 25.6 ± 6.3%. In conclusion, %FMD did not plateau with increasing SR, therefore no ceiling was identified. The inflection in slope may indicate the involvement of different or additional vasodilator mechanisms post-threshold. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2011-09-15 20:17:11.582

abstract: ABSTRACT Despite significant advancements in drug therapy, cardiovascular disease (CVD) is still the leading cause of death in the United States. Given this, research has begun to seek out alternative approaches to reduce CVD risk. One of these alternative approaches is Vitamin D supplementation. Current research has shown a link between Vitamin D status and CVD risk in both healthy and diseased populations. Among the possible mechanisms is a positive effect of Vitamin D on vascular endothelial function, which can be measured with noninvasive techniques such as flow-mediated dilation (FMD) of conduit vessels using high-resolution ultrasound. This dissertation is comprised of two studies. The first examines whether Vitamin D supplementation can improve FMD in older adults within a time period (two weeks) associated with peak increases in plasma Vitamin D concentrations after a single-dose supplementation. The second examines the effect of Vitamin D supplementation in people with Rheumatoid Arthritis (RA). The reason for looking at an RA population is that CVD is the leading cause of early mortality in people with RA. In the first study 29 Post-Menopausal Women received either 100,000 IU of Vitamin D3 or a Placebo. Their FMD was measured at baseline and 2 weeks after supplementation. After 2 weeks there was a significant increase in FMD in the Vitamin D group (6.19 + 4.87 % to 10.69 + 5.18 %) as compared to the Placebo group (p=.03). In the second study, 11 older adults with RA were given 100,000 IU of Vitamin D or a Placebo. At baseline and one month later their FMD was examined as well as plasma concentrations of Vitamin D and tumor necrosis factor-alpha; (TNF-alpha;). They also filled out a Quality of Life Questionnaire and underwent a submaximal exercise test on the treadmill for estimation of maximum oxygen uptake (VO2max). There was no significant change in FMD in Vitamin D group as compared to the Placebo group (p=.721). Additionally, there was no significant improvement in either plasma Vitamin D or TNF-alpha; in the Vitamin D group. There was however a significant improvement in predicted VO2max from the submaximal exercise test in the group receiving Vitamin D (p=.003). The results of these studies suggest that a single 100,000 IU dose of Vitamin D can enhance FMD within two week in older adults, but that a similar dose may not be sufficient to increase FMD or plasma Vitamin D levels in older adults with RA. A more aggressive supplementation regimen may be required in this patient population. / Dissertation/Thesis / Ph.D. Exercise and Wellness 2012

No description available.

The development of atherosclerotic lesions and endothelial cell damage can originate during early childhood. Endothelial cells produce and release vasodilatory chemicals, which dictate the artery’s ability to vasodilate or vasoconstrict. Brachial artery FMD is a non-invasive, reproducible and a sensitive technique used to detect changes in arterial diameter and is correlated with coronary artery endothelial function. Cross-sectional studies have indicated increases in arterial diameter in children between the ages of 6-18 years however, a longitudinal, observational design study has not been conducted to understand how arterial diameters and FMD change over time in children, with considerations for the influences of physical activity and sex. The purpose of this study was to understand the impact of age and sex on arterial diameter and FMD and investigate the effects of habitual moderate-to-vigorous physical activity (MVPA) during both the school-age and preschool years on endothelial function trajectories during the school-age years. Over three years, 418 children between 3-5 years old participated in the HOPP study annually, and 279 of these children attended the lab when they were between 6-12 years old for an additional 3 annual visits in the SKIP study. Habitual MVPA was measured for 7 days in both the HOPP and SKIP studies each year, and FMD was measured each year during SKIP. Linear mixed-effects modeling was implemented to study the trend in FMD and the influence of chronological and biological age, sex and MVPA on arterial function; effects are reported as unstandardized estimates (Est). Boys had larger baseline and peak brachial artery diameters compared to girls (p<0.001). Girls had larger brachial artery FMD compared to boys (6.82±3.39 vs. 6.23±3.50 %, p<0.001). There was an effect of MVPA in the SKIP study on allometrically scaled FMD (Est. -0.017, p=0.03), but not on relative FMD (Est. -0.01, p=0.17). MVPA in the preschool years did not predict school-aged scaled FMD (Est. 0.11, p=0.24) or FMD (Est. -0.003, p=0.64). The observed trends in brachial artery diameter and FMD are in-line with expected changes in growth and maturation in children. Children who engaged in more habitual MVPA during the childhood years, but not the preschool years, demonstrated changes endothelial function during the school-age years. / Thesis / Master of Science (MSc) / It is clear that preliminary signs of atherosclerosis begin during the early years of childhood, and typically precede the development of future cardiovascular disease. Engaging in habitual physical activity at higher intensities, has been shown to positively influence cardiovascular health, specifically in central and peripheral arteries. This study sought to investigate the trends in vascular heath over time in children and examine the effect of moderate-to-vigorous physical activity engagement during the preschool years on vascular health during the school-age years. Our results suggest that as children age, their arteries get bigger in size and that school-aged girls have elevated vascular function when compared to boys. Children who engage in greater amounts of moderate-to-vigorous physical activity during their school-age years does not influence measures of vascular health. Additionally, engagement in habitual moderate to vigorous physical activity during the preschool years does not impact these vascular health relationships during the school-age years.

Distortion to hemodynamic, ischemic and metabolic stimuli during low load resistance exercise with blood flow restriction (BFR) may influence regional vascular adaptation. This thesis investigated the acute response and chronic adaptations of the peripheral vasculature to low load resistance exercise with BFR. The methodology utilised Doppler ultrasound, strain gauge plethysmography and muscle biopsy for insightful measures of the vasculature at different regions of the arterial tree. Short term (4-6 weeks) localised low load (30-40% 1RM) resistance exercise with BFR increased brachial (3.1%) and popliteal (3.3%) artery maximal diameter (in response to ischemic exercise), forearm (29%) and calf (24%) post-occlusive blood flow, and calf filtration capacity (14%). These findings indicate potential vascular remodelling at the conduit (chapters 3, 4) resistance (chapter 4) and capillary (chapter 4) level of the vascular tree. Regional, rather than systemic, factors are responsible for these adaptations as evidenced by an absent response in the contralateral control limb. Transient improvements in popliteal artery FMD% occurred at week 2 before increased maximal diameter at week 6, suggesting functional changes precede structural remodelling (chapter 4). Maximal brachial artery diameter and forearm post-occlusive blood flow returned to baseline values after a 2 week detraining period, signifying rapid structural normalisation after stimulus removal (chapter 3). Enhanced capillarity, despite low training loads, could be explained by augmentation of VEGF (~7 fold), PGC-1α (~6 fold) and eNOS (~5 fold) mRNA, and upregulation VEGFR-2 (~5 fold) and HIF-1α (~2.5 fold) mRNA with BFR (chapter 5). This indicates a targeted angiogenic response potentially mediated through enhanced metabolic, ischemic and shear stress stimuli. Large between subject variability in the level of BFR was observed during upper and lower limb cuff inflation protocols. Adipose tissue thickness and mean arterial pressure were the largest independent determinants of upper and lower limb BFR, respectively (Chapter 6). In conclusion, this thesis demonstrates that low load resistance exercise with BFR induces adaptation in the conduit, resistance and capillary vessels. The mediators of this response are likely to be the hemodynamic and chemical signals elicited by repeated bouts of BFR resistance exercise, although confirmation of these mechanisms is required. The functional significance of these adaptations is unknown and warrants further investigation.

Exercise training promotes a beneficial endothelial cell (EC) phenotype and results in conduit vessel adaptation. The specific underlying mechanisms have been proposed (shear stress, circumferential stress, hypoxia, metabolic) but are yet to be fully elucidated. This thesis investigated the predominant stimuli responsible for conduit vessel adaptation with training. Further, it developed a method of in situ EC extraction to allow for determination of the cellular and molecular mechanisms underpinning these adaptations. The methodology utilised two-dimensional (2D) Doppler ultrasound, strain gauge plethysmography, immunocytochemistry and RT-qPCR to provide insight in to vascular characteristics, predominantly of the brachial artery and peripheral EC. Long-term repeated isometric forearm muscle contractions as performed by well-trained rock climbers promoted greater resting, peak (in response to 5 min ischaemia) and maximal (in response to ischaemic exercise) brachial artery diameters compared with controls. This structural response is dependent upon confounders associated with exercise additional to shear stress as evidenced by the lack of brachial artery remodelling in response to 8 weeks of ischaemic preconditioning (IPC). A transient increase in flow-mediated dilation (FMD)% was observed following 6 weeks exposure to IPC, which became significant when controlled for baseline artery diameter, despite an absence of augmentation following long-term (≥ 8 weeks) exposure to a shear stimulus. This is in line with the suggested timeline of conduit vessel adaptation to exercise training of a transient increase in function at 2-4 weeks. Underpinning molecular mechanisms responsible were not determined but may be further investigated given that the endovascular biopsy technique was developed and improved in this thesis. The endovascular biopsy successfully yields approximately 2100 ± 1700 EC per sample, providing sufficient material for determination of expression of both mRNA (RT-qPCR) and protein (immunocytochemistry). Specifically, type 2 diabetics (T2DM) with symptomatic cardiac abnormalities exhibited augmented eNOS mRNA and protein in brachial artery EC as compared with non-diabetic controls with symptomatic cardiac abnormalities. In conclusion, this thesis demonstrates that although shear stress promotes a transient trend for enhancement in function of the peripheral conduit arteries, additional factors are required for long-term structural adaptations. Further, the endovascular biopsy technique offers a novel method of extracting and analysing EC for genes and proteins of interest to vascular health. The use of this technique to decipher the underlying cellular and molecular mechanisms involved in vascular adaptations with exercise requires further investigation.

Introdução. A prática regular do exercício de força (EF) está associada a adaptações metabólicas, neuromusculares e cardiovasculares que repercutem de maneira positiva sobre a saúde e qualidade de vida de seus praticantes. No entanto, Indivíduos sedentários apresentam comprometimentos agudos na função endotelial após EF de alta intensidade. Objetivo. Avaliar a função endotelial de indivíduos sedentários de meia idade em resposta a diferentes intensidades do EF. Métodos. 11 indivíduos sedentários (40,1±3,9 anos; 27,3±1,4 kg/m2) realizaram EF em três condições experimentais: extensão de joelhos a 50% de 1RM (MI), 80% de 1RM (AI) e repouso na condição controle (CON). Foi realizada avaliação da vasodilatação mediada pelo fluxo (FMD) antes, 30 minutos após e 60 minutos após os protocolos. A quantificação das concentrações de NO2 e NO3 (NOx), endotelina-1 (ET-1) e TBARS foram realizadas antes, imediatamente após e 60 minutos após os protocolos. A pressão arterial foi mensurada antes e após os protocolos Resultados. A FMD aumentou significativamente 30 minutos após o exercício na condição MI (12,5± 4,10 para 17,2±3,9 %; p=0,01) bem como os níveis de NOx (6,8± 3,3 vs. 12,6± 4,2μM; p= 0,007). A concentração de ET-1 aumentou imediatamente após na condição AI (20,02±2,2 vs. 25,4± 2,1pg/ml; p= 0,004). A elevação da pressão arterial não diferiu entre as condições MI e AI. As concentrações de TBARS não se alteraram ao longo dos protocolos. Conclusão. O EF de moderada intensidade aumenta a FMD e os níveis NOx após uma sessão aguda de exercício em indivíduos sedentários de meia idade, estes resultados sugerem que menores intensidades do EF são mais seguras ao iniciar um programa de exercícios. / Regular resistance exercise (RE) is associated with metabolic, neuromuscular and cardiovascular adaptation that results in improvement of quality of life and health. However, sedentary subjects have been showing an acute impairment on endothelial function after high intensity resistance exercise. The aim of this study was to evaluate the endothelial function in sedentary middle age men after RE in different intensities. Methods. Eleven middle age sedentary men (40,1±3,9 years; 27,3±1,4 kg/m2) performed RE in three different conditions: knee extension at 50% of one 1RM (MI), at 80% of 1RM (HI) and rest in the control group (CON). Flow mediated dilation (FMD) was assessed before, 30 and 60 minutes of exercise. Venus plasma concentration of ET-1 NOx and TBARS were measured before, immediately after and 60 minutes after exercise. Blood pressure was evaluated before and after exercise. Results. There was a significant improvement in FMD 30 minutes after exercise in the MI condition (12,5± 4,10 vs 17,2±3,9%; p= 0,016; p=0,01). The plasma NOx concentration was significant higher immediately after MI (6,8± 3,3 vs. 12,6± 4,2μM; p= 0,007). There was a significant improvement in the plasma ET-1 concentration immediately after HI (20,02±2,2 vs. 25,4± 2,1pg/ml; p= 0,004). There was no significant difference in the BP between the experimental conditions (MI vs HI) and TBARS throughout the experimental conditions. Conclusions. Resistance exercise performed in moderate intensity improve endothelial function in sedentary middle aged men, there results suggest that lower intensities of RE could be safe for this population in the beginning of the exercise programs.

The endothelium plays an essential role in the regulation of vascular homeostasis and a state of endothelial dysfunction, which develops in the presence of cardiovascular risk factors, may contribute to the development and progression of cardiovascular disease. As such, the measurement of endothelial function, beyond being an experimental tool, may serve as an important tool to complement current risk assessment algorithms in the identification of high-risk patients. Flow-mediated dilation (FMD) is a non-invasive measure of peripheral conduit artery endothelial function that holds great promise. Presently, FMD suffers from methodological heterogeneity and a poor understanding of the various biological components involved in eliciting the dilatory response to a given shear stimulus. We compared both traditional and alternative methods of arterial diameter characterization with regards to their repeatability, nitric oxide-dependency, and their sensitivity in distinguishing between normal and dysfunctional endothelial responses. Our findings emphasize the importance of continuous arterial diameter measurement and suggest that the time to peak FMD is not a useful adjunctive measure of the FMD response. Given that endothelial dysfunction may be of clinical importance, strategies to correct it or prevent it from occurring may be of benefit. The 3-hydroxy-3-methylglutaryl coenzyme A inhibitors are agents that have demonstrated marked cholesterol-independent, endothelial-protective effects. We investigated the ability of rosuvastatin and atorvastatin to protect against endothelial dysfunction associated with ischemia and reperfusion (IR) injury, and chronic nitrate therapy. Using the FMD technique, we demonstrated, for the first time in humans, that acute rosuvastatin administration protects against IR-induced conduit artery endothelial dysfunction. Additionally, we demonstrated that this effect likely occurred by a cyclooxygenase-2-dependent mechanism, which may provide mechanistic insight into the observed cardio-toxicity with cyclooxygenase-2 inhibitors. In contrast, we observed that this endothelial-protective effect was lost upon sustained rosuvastatin administration, which may have important implications regarding the generation of sustained cardioprotective phenotypes. Finally, we demonstrated that atorvastatin co-administration prevented the development of tolerance and endothelial dysfunction associated with continuous transdermal nitroglycerin therapy in humans, likely through an antioxidant mechanism. Future studies are needed in disease patients to determine whether the concept of nitrate tolerance needs reconsideration in the presence of vascular-protective agents.

The endothelium plays an essential role in the regulation of vascular homeostasis and a state of endothelial dysfunction, which develops in the presence of cardiovascular risk factors, may contribute to the development and progression of cardiovascular disease. As such, the measurement of endothelial function, beyond being an experimental tool, may serve as an important tool to complement current risk assessment algorithms in the identification of high-risk patients. Flow-mediated dilation (FMD) is a non-invasive measure of peripheral conduit artery endothelial function that holds great promise. Presently, FMD suffers from methodological heterogeneity and a poor understanding of the various biological components involved in eliciting the dilatory response to a given shear stimulus. We compared both traditional and alternative methods of arterial diameter characterization with regards to their repeatability, nitric oxide-dependency, and their sensitivity in distinguishing between normal and dysfunctional endothelial responses. Our findings emphasize the importance of continuous arterial diameter measurement and suggest that the time to peak FMD is not a useful adjunctive measure of the FMD response. Given that endothelial dysfunction may be of clinical importance, strategies to correct it or prevent it from occurring may be of benefit. The 3-hydroxy-3-methylglutaryl coenzyme A inhibitors are agents that have demonstrated marked cholesterol-independent, endothelial-protective effects. We investigated the ability of rosuvastatin and atorvastatin to protect against endothelial dysfunction associated with ischemia and reperfusion (IR) injury, and chronic nitrate therapy. Using the FMD technique, we demonstrated, for the first time in humans, that acute rosuvastatin administration protects against IR-induced conduit artery endothelial dysfunction. Additionally, we demonstrated that this effect likely occurred by a cyclooxygenase-2-dependent mechanism, which may provide mechanistic insight into the observed cardio-toxicity with cyclooxygenase-2 inhibitors. In contrast, we observed that this endothelial-protective effect was lost upon sustained rosuvastatin administration, which may have important implications regarding the generation of sustained cardioprotective phenotypes. Finally, we demonstrated that atorvastatin co-administration prevented the development of tolerance and endothelial dysfunction associated with continuous transdermal nitroglycerin therapy in humans, likely through an antioxidant mechanism. Future studies are needed in disease patients to determine whether the concept of nitrate tolerance needs reconsideration in the presence of vascular-protective agents.

Introdução. A prática regular do exercício de força (EF) está associada a adaptações metabólicas, neuromusculares e cardiovasculares que repercutem de maneira positiva sobre a saúde e qualidade de vida de seus praticantes. No entanto, Indivíduos sedentários apresentam comprometimentos agudos na função endotelial após EF de alta intensidade. Objetivo. Avaliar a função endotelial de indivíduos sedentários de meia idade em resposta a diferentes intensidades do EF. Métodos. 11 indivíduos sedentários (40,1±3,9 anos; 27,3±1,4 kg/m2) realizaram EF em três condições experimentais: extensão de joelhos a 50% de 1RM (MI), 80% de 1RM (AI) e repouso na condição controle (CON). Foi realizada avaliação da vasodilatação mediada pelo fluxo (FMD) antes, 30 minutos após e 60 minutos após os protocolos. A quantificação das concentrações de NO2 e NO3 (NOx), endotelina-1 (ET-1) e TBARS foram realizadas antes, imediatamente após e 60 minutos após os protocolos. A pressão arterial foi mensurada antes e após os protocolos Resultados. A FMD aumentou significativamente 30 minutos após o exercício na condição MI (12,5± 4,10 para 17,2±3,9 %; p=0,01) bem como os níveis de NOx (6,8± 3,3 vs. 12,6± 4,2μM; p= 0,007). A concentração de ET-1 aumentou imediatamente após na condição AI (20,02±2,2 vs. 25,4± 2,1pg/ml; p= 0,004). A elevação da pressão arterial não diferiu entre as condições MI e AI. As concentrações de TBARS não se alteraram ao longo dos protocolos. Conclusão. O EF de moderada intensidade aumenta a FMD e os níveis NOx após uma sessão aguda de exercício em indivíduos sedentários de meia idade, estes resultados sugerem que menores intensidades do EF são mais seguras ao iniciar um programa de exercícios. / Regular resistance exercise (RE) is associated with metabolic, neuromuscular and cardiovascular adaptation that results in improvement of quality of life and health. However, sedentary subjects have been showing an acute impairment on endothelial function after high intensity resistance exercise. The aim of this study was to evaluate the endothelial function in sedentary middle age men after RE in different intensities. Methods. Eleven middle age sedentary men (40,1±3,9 years; 27,3±1,4 kg/m2) performed RE in three different conditions: knee extension at 50% of one 1RM (MI), at 80% of 1RM (HI) and rest in the control group (CON). Flow mediated dilation (FMD) was assessed before, 30 and 60 minutes of exercise. Venus plasma concentration of ET-1 NOx and TBARS were measured before, immediately after and 60 minutes after exercise. Blood pressure was evaluated before and after exercise. Results. There was a significant improvement in FMD 30 minutes after exercise in the MI condition (12,5± 4,10 vs 17,2±3,9%; p= 0,016; p=0,01). The plasma NOx concentration was significant higher immediately after MI (6,8± 3,3 vs. 12,6± 4,2μM; p= 0,007). There was a significant improvement in the plasma ET-1 concentration immediately after HI (20,02±2,2 vs. 25,4± 2,1pg/ml; p= 0,004). There was no significant difference in the BP between the experimental conditions (MI vs HI) and TBARS throughout the experimental conditions. Conclusions. Resistance exercise performed in moderate intensity improve endothelial function in sedentary middle aged men, there results suggest that lower intensities of RE could be safe for this population in the beginning of the exercise programs.