Maternal and fetal stressors during development can permanently alter various physiological functions and impact long-term health. These alterations are said to be programmed because they persist long after the original insult. Current evidence indicates that iron deficiency (ID) during pregnancy can induce a host of long-term programming effects, including cardiovascular complications and behavioural deficits. Despite the relevance of ID as a model of developmental programming, these effects have not been extensively studied. The purpose of the present series of experiments was to develop a model of maternal ID throughout pregnancy to study its long-term cardiovascular and behavioural consequences in neonatal and adult offspring. Female rats were fed either a low iron diet (3 mg/kg or 10 mg/kg Fe) or a control diet (> 225 mg/kg Fe) prior to and throughout gestation. At birth, all dams were fed a control diet (270 mg/kg Fe). This treatment caused altered growth trajectories which persisted in adulthood. Adult perinatal ID (PID) offspring, despite showing no signs of anemia at that time, had persistent elevations in arterial pressure (AP), as well as enhanced responsiveness of AP to high and low sodium intake. These animals also had altered responsiveness of renal medullary blood flow to changes in AP. PID offspring also had altered function of intrarenal and vascular nitric oxide signaling. Similar studies performed in acute ID animals revealed opposite trends in intrarenal and vascular NOS function, as well as in effects on the cardiovascular system. In addition to the cardiovascular effects, adult PID male offspring exhibited a number of behavioural changes, as assessed by monitoring locomotor activity in their home cages (by radiotelemetry) as well as in a novel environment. PID male offspring also performed poorly in a Morris water maze compared to controls. These differences were not observed in female PID animals. In summary, these studies provide evidence that ID during gestation has deleterious effects on various aspects of the offspring’s physiology. Given the global incidence of ID, as well as its propensity to afflict pregnant women, developmental programming from this condition could have profound implications on global health. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2009-01-22 23:32:40.931

Cognitive impairment no dementia (CIND) is conceptualized as a stage of cognitive decline between normal aging and onset of dementia. As persons with CIND are at high risk of developing dementia, efforts to determine early predictors of cognitive decline are warranted to advance both clinical knowledge and practice. Recent evidence suggests persons with CIND may have changes in vascular function compared to non-impaired peers, which may have clinical potential to differentiate those with and without CIND. The purpose of this study is to determine whether vascular functioning, examined both by individual indicators and as an aggregate vascular factor, will be associated with cognitive impairment. It is expected that the individual vascular indicators of hypertension, diabetes, stroke, and heart problems will be related to cognitive status classification, with poorer vascular function being more strongly associated with CIND as compared to the control group. Further, it is expected that examining the aggregate vascular factor in a multivariate approach will be more strongly associated with cognitive status than examining the vascular indicators individually. Data for this study were collected in the Victoria Longitudinal Study (VLS), a large-scale longitudinal, sequential study of community-dwelling older adults in Victoria, British Columbia. Cognitive group status was determined by a distributional approach based on scores on 5 cognitive reference measures. The associations between all vascular factors and cognitive status groups were assessed using chi-square analyses. Univariate analyses were then carried out using ordinal logistic analysis. A multivariate approach using discriminant analysis was then used to determine if cognitive status group membership was associated with vascular function based on linear combinations of vascular indicators. Contrary to expected results, we did not find a significant association between any of the vascular indicators (i.e., blood pressure classification, severity of stroke, severity of heart troubles, and severity of diabetes) and the cognitive status classifications. Further, group membership was not associated with any of the individual vascular markers, or by a multivariate combination of the indicators. Several reasons for this study’s findings include discrepant definitions of cognitive impairment in the literature, sample characteristics (i.e. high education, low base rate of vascular problems), and methodological considerations. Future research objectives should address the longitudinal association of vascular function and cognitive status. / Graduate

Regular soy consumption has been shown to reduce cardiovascular (CV) risk through plasma cholesterol reduction. According to the current health claim, this benefit is attributed to soy protein (SP). Dietary intervention trials indicate that isoflavones (ISO), weak phytoestrogens in soy, may also contribute by offering additional vascular and metabolic protection. Equol, a metabolite of the ISO daidzein (DAZ) with greater estrogenic potency, may be an important mediator of such effects. This thesis examines effects of soy, in particular, ISO consumption on CV risk factors and the potential for ISOs to enhance cognition, possibly through improvements of circulatory function. Two crossover design intervention trials were undertaken: a food-based intervention, investigating differential effects of SP and ISO on plasma lipids and other risk factors for CVD, and an ISO supplementation trial, examining effects on cognition and vascular function. Both addressed whether benefits were dependent on equol production. In the first trial, 91 subjects with untreated mild hypercholesterolemia were randomised to consume each of the following three diets in random order for sequential 6 week periods: (S) soy foods containing 24 g of SP and 75-90 mg ISO per day, (SD) soy/dairy foods containing 12 g SP, 12 g dairy protein (DP) and 75-90 mg ISO per day or (D) dairy foods containing 24 g DP only per day. At the end of each diet period, blood lipids, flow-mediated dilatation (FMD) of the brachial artery, blood pressure, arterial compliance and anthropometric measures were assessed. Compared with the control diet (D), there was a small but significant reduction in total cholesterol on the S diet only (2.8 + 1.1%, P<0.05), which could be accounted for by a decrease in saturated fat intake. FMD was found to be significantly improved when SD and S diet data were nested (P=0.03). Plasma triglycerides (TG) improved on both the SD and S diets compared with D (P<0.01). Other lipid, metabolic and vascular parameters did not differ between diets. There were no differences in outcomes between equol (n=30) and non equol producers (n=61). In a subsequent 12 week double-blind supplementation trial, 34 healthy males were randomised to take 4 capsules providing 120mg ISO per day or a matching placebo for 6 weeks, after which they crossed over to the alternate supplement. FMD and cognitive assessments relating to measures of memory and executive function were performed at the beginning and end of each treatment phase. Spatial working memory, a test in which females consistently perform better than males, was significantly improved by ISO supplementation (P<0.02). However, other measures of cognition and FMD were unaffected and there were no differences between equol (n=8) and non-equol producers (n=26). These interventions indicate that ISOs offer specific health benefits, independent of equol production. ISO supplementation can enhance specific cognitive processes which appear dependent on estrogen activation. Additionally, soy foods containing ISOs improved FMD and TG but were unable to improve LDL cholesterol, even in equol producers. Thus dietary ISOs may reduce CV risk but the validity of the current health claim for SP is questioned. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1345614 / Thesis (Ph.D.) - University of Adelaide, School of Molecular and Biomedical Science, 2008

No description available.

Heat therapy may be an alternative or adjunct intervention to exercise training for improving cardiovascular function and health. However, its prescription must be refined in order to overcome the feasibility and tolerability issues associated with current whole-body heating modes. There is substantial evidence to support the beneficial effects of high doses (e.g., frequency, duration, and intensity) of heating typically achieved using whole-body modes, but there is limited knowledge on whether lower doses of heating administered through local hot water immersion of the limbs can still have an impact on vascular function. All studies were conducted in heathy young men and women. In the first study, we found that regardless of whether local heating was applied to the lower limbs up to the ankles or knees, upper limb endothelial function and lower limb arterial stiffness improved acutely. In the second study, we proceeded to prescribe ankle-level heating in a chronic intervention and compared its effects to that of moderate-intensity cycling exercise training. We observed no changes in endothelial function, but decreases in central arterial stiffness and increases in cardiorespiratory fitness in those who performed heat therapy and exercise training combined with heat therapy. In the third study, we evaluated the ability of acute vascular function responses to predict chronic vascular function responses with heating and exercise interventions, and found significant positive associations between the acute and chronic responses for absolute and relative brachial artery flow-mediated dilation and femoral-foot pulse wave velocity. These findings suggest that, in healthy young men and women, local heating through ankle-level hot water immersion can improve indices of cardiovascular function both acutely and chronically, alone or combined with exercise training. Further, acute responses may be used to determine an individual’s chronic responsiveness to a heat therapy and/or exercise training intervention. More research in larger, more diverse samples and with a longer duration of therapy and/or training should be conducted to determine if the results are replicable. / Dissertation / Doctor of Philosophy (PhD) / Regular participation in whole-body heat therapy can extend health and life span, but it is used infrequently because of a lack of feasibility from a cost, accessibility, and tolerability standpoint. This thesis explored whether local heat therapy in young healthy men and women would be effective for improving blood vessel health defined as endothelial function and arterial stiffness, both of which are linked to the risk of developing many chronic diseases. Furthermore, the effects of local heat therapy were compared to that of exercise training. We found that there were beneficial short- and long-term effects of lower limb hot water immersion that manifested in different areas of the body. Local heat therapy improved upper limb endothelial function and lower limb arterial stiffness immediately after a session, whereas with repeated exposure, it may have improved central arterial stiffness and cardiorespiratory fitness. Exercise training only had beneficial effects on the blood vessels when combined with heat therapy. Finally, short-term vascular responses can predict long-term vascular responses to both heat therapy and/or exercise training. Overall, our findings suggest that there may be some utility for local heat therapy to promote healthy blood vessels, but more work must be done to replicate our findings and explore its effects on other populations.

No description available.

Yes / This study describes the screening of 13 commercially-available plant extracts for pharmacological activity modulating vascular function using an endothelial cell model. A French maritime pine bark extract (FMPBE) was found to have the greatest effect upon nitric oxide availability in control (181% ± 36% of untreated cells) and dysfunctional cells (132% ± 8% of untreated control cells). In healthy volunteers, the FMPBE increased plasma nitrite concentrations 8 h post-consumption compared to baseline (baseline corrected median 1.71 ± 0.38 (25% IQR) and 4.76 (75% IQR) µM, p < 0.05). This was followed by a placebo-controlled, healthy volunteer study, which showed no effects on plasma nitrite. It was confirmed that different batches of extract had been used in the healthy volunteer studies, and this second batch lacked bioactivity, assessed using the in vitro model. No difference in plasma catechin levels was seen at 8 h following supplementation between the studies (252 ± 194 nM versus 50 ± 64 nM, p > 0.05), however HPLC-UV fingerprinting showed that the new batch had a 5-15% in major constituents (including procyanidins A2, B1 and B2) compared to the original batch. This research describes a robust mechanism for screening bioactive extracts for vascular effects. It also highlights batch variability as a significant limitation when using complex extracts for pharmacological activity, and suggests the use of in vitro systems as a tool to identify this problem in future studies.

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.

Exposure to air pollution, particularly fine and ultrafine particulate matter derived from combustion sources, has been consistently associated with increased cardiovascular morbidity and mortality. Recent controlled exposure studies demonstrate that short-term exposure to diesel exhaust, which can contribute up to 40% of urban particulate air pollution, results in impaired vascular endothelial and fibrinolytic function in healthy volunteers, and increased exercise-induced myocardial ischaemia in patients with coronary heart disease. These observations may, in part, explain the observed increase in cardiovascular events following exposure to air pollution. Despite these observations there remain uncertainties regarding the key constituents of the air pollution mixture that mediate these adverse effects, and the underlying physiological and biological pathways involved. In these studies, using two controlled exposure facilities, I explored the vascular effects of the most prevalent gaseous component of the air pollution mixture – nitrogen dioxide – and the mechanisms responsible for impaired vasomotor function following exposure to diesel exhaust. Furthermore, I investigated the effect of acute exposure to “real-world” urban air pollution in both healthy volunteers and patients with coronary heart disease, and the effect of reducing that exposure using a simple facemask. In total, 10 healthy volunteers were exposed to nitrogen dioxide, and 29 healthy volunteers exposed to dilute diesel exhaust in a series of doubleblind randomised crossover studies. Exposure to nitrogen dioxide had no effect on either vasomotor function or endogenous fibrinolysis, providing indirect evidence that the adverse vascular effects are predominantly driven by particulate components. Following exposure to diesel exhaust there was no up regulation of endothelin-1 production, although there was increased vasoconstriction to intra-arterial infusion of endothelin-1. Following endothelin A receptor antagonism, there was attenuated vasodilatation following exposure to diesel exhaust as compared to air, an effect abrogated by endothelin B receptor antagonism. My findings suggest that the endothelin system does not play a central role in the adverse vascular effects of air pollution, but given the tonic interaction between the endothelin and nitric oxide systems, these observations could be explained by reduced nitric oxide bioavailability. Following diesel exhaust inhalation, plasma nitrite concentrations (as a marker for nitric oxide generation) are markedly increased without changes in haemodynamics or basal blood flow consistent with increased nitric oxide consumption. In the presence of a nitric oxide clamp, and without endogenous nitric oxide release, the vascular responses to vasodilators are similar. This perturbation of nitric oxide consumption and release appears to underlie the observed vascular endothelial effects. Fifteen healthy volunteers and 98 patients with coronary artery disease were recruited in Beijing, China. Subjects walked along a predefined city centre route for 2 hours in the presence and absence of a highly efficient facemask to reduce personal particulate air pollution exposure in an open label randomised crossover study. When wearing a facemask, there was an attenuation of exercise-induced increases in blood pressure, an improvement in heart rate variability, reduced myocardial ischaemia and subjects reported fewer symptoms. My findings have identified the biological mechanisms underlying the adverse vascular effects of exposure to diesel exhaust, and have helped to clarify the components responsible for these effects. Moreover, I have identified important benefits of reducing personal exposure to particulate matter using a simple facemask that have the potential to reduce cardiovascular events in patients living in urban or industrialised areas. Ongoing research in this area will provide further insight into the underlying vascular mechanisms, and the potential benefits of reducing particulate air pollution exposure, and may result in important targeted interventions to reduce the impact of air pollution on cardiovascular health.

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.