Medical Sciences Commons^™

The Sympathetic Neural Control Of The Circulation At Rest And During Exercise: Effects Of Age, Biological Sex, And Sex Hormones, Andrew W. D'Souza

Electronic Thesis and Dissertation Repository

The overall objective of this dissertation was to determine the impact of age, sex, and sex hormones on the discharge behaviours of muscle sympathetic action potentials (APs) as well as the corresponding changes in peripheral vasoconstriction and blood pressure at rest and during exercise. The microneurographic technique was employed to record multi-unit muscle sympathetic nerve activity (MSNA), with a continuous wavelet transform applied post-hoc to evaluate APs within the recorded neurogram. Study One examined the impact of aging on the central and peripheral arcs of the sympathetic baroreflex under resting conditions. This study revealed that middle-aged-to-older adults demonstrated heightened sympathetic …

Exploration Of The Pathophysiological Mechanisms Underlying Hemodialysis Associated Cardiac Ischemic Injury, Lisa Yun Jeong Hur

Electronic Thesis and Dissertation Repository

Hemodialysis (HD) provides life-saving treatment in individuals with kidney failure. However, HD is associated with poor quality of life and extremely high mortality rates mainly caused by cardiovascular disease due to heart failure and sudden cardiac death. Standard pharmacological treatment developed within the non-kidney disease community are largely ineffective in HD patients because of the difference in pathophysiology of cardiovascular mortality. HD treatment causes hypotension and recurrent ischemic injury to multiple vascular beds including the heart, leading to heart failure. These injuries can be abrogated by improving the patient’s tolerability of the treatment. To apply interventions that may improve hemodynamic …

Endothelial Dysfunction In Hindlimb Arteries Of Old Sprague Dawley Rats, And The Type 2 Diabetic Zucker Diabetic Sprague Dawley Strain., Andrea N. Wang

Electronic Thesis and Dissertation Repository

Ageing, and type 2 diabetes are associated with cardiovascular diseases and endothelial dysfunction. Endothelial dysfunction is characterized by a decline in endothelium-mediated vasodilation. In this thesis, we determined the vascular function of hindlimb arteries supplying skeletal muscle and extremities using isolated arteries and wire myography. For ageing studies, we used Sprague Dawley rats and for type 2 diabetes we used the Zucker Diabetic Sprague Dawley strain. Vasodilation of hindlimb arteries with acetylcholine were impaired in both models. However, protease-activated receptor 2 mediated vasodilation was upregulated in arteries. Evidence of non-nitric oxide mechanisms were also found in peripheral vasculature. These data …

Exogenous Surfactant As A Delivery Vehicle For Intrapulmonary Therapeutics, Brandon J. Baer

Electronic Thesis and Dissertation Repository

As an organ system, the lung has unique advantages and disadvantages for direct drug delivery. Its contact with the external environment allows for the airways to be easily accessible to intrapulmonary delivery. However, its complex structure, which divides into more narrow airways with each branch, can make direct delivery to the remote alveoli challenging. The objective of this thesis was to overcome this issue by using exogenous surfactant, a lipoprotein complex used to treat neonatal respiratory distress syndrome, as a carrier for pulmonary therapeutics. It was hypothesized that therapeutics administered with a surfactant vehicle would display enhanced delivery to the …

Cerebrovascular Compliance In Humans, Marcy Erin Moir

Electronic Thesis and Dissertation Repository

Pulsatile blood flow consists of two components: steady flow and oscillatory flow. Steady blood flow is primarily regulated by vascular resistance while vascular compliance represents a key mediator of oscillatory blood flow. However, most studies investigating the regulation of cerebral blood flow in humans have focused on vascular resistance. Recently, emerging evidence has implicated vascular compliance as an important contributor to the regulation of cerebral perfusion. Therefore, the research contained herein aimed to i) quantify cerebrovascular compliance responses to blood pressure alterations and ii) explore mechanisms regulating cerebrovascular compliance in humans. The studies employed a Windkessel modelling approach to calculate …

Experimental, Theoretical, And Translational Studies Of Rbc Distribution In Capillary Networks, Asher Mendelson

Electronic Thesis and Dissertation Repository

The purpose of this thesis was to evaluate the physiology of red blood cell (RBC) distribution in skeletal muscle capillary networks. Because this is the terminal site of oxygen exchange in the microcirculation, characterization of this fundamental process informs an understanding of how microvascular blood flow regulation matches oxygen supply with local tissue demand. Prior studies in this field have focused on small groups of capillaries, and have not linked capillary network structure with functional measurements, nor evaluated the temporal complexity of RBC distribution over physiologically-relevant scales. It is also unclear how the functional units called capillary modules – comprised …

The Role Of Timp3 In Microvascular Endothelial Cell-Extracellular Matrix Interaction And Regulation Of Microvascular Barrier Function, Nidhi Kulkarni

Electronic Thesis and Dissertation Repository

Pulmonary microvascular endothelial cell (PMVEC) interactions with the extracellular matrix (ECM) mediates PMVEC barrier function. Further, data suggests an association between decreased PMVEC-ECM interactions under proinflammatory conditions and PMVEC barrier dysfunction. Tissue inhibitor of metalloproteinases 3 (TIMP3) may also regulate barrier function, as PMVEC from Timp3^-/-mice show increased leak. Studies in the developing lung also showed TIMP3 regulating PMVEC-ECM interactions. Based on this, I hypothesized that TIMP3 maintains PMVEC barrier function by promoting PMVEC-ECM interactions.

Using the XperT-permeability assay, Timp3^-/-PMVEC demonstrated enhanced leak vs. WT PMVEC, particularly under proinflammatory conditions, and this was associated with decreased …

Vascular Stiffening And The Brain: Direct Measures Of Cerebrovascular Stiffness In Aging And Vasodilation, Christopher S. Balestrini

Electronic Thesis and Dissertation Repository

Dampening of pulsatile pressure waves within blood vessels is an essential feature of the arterial system. Vascular stiffening increases the speed and the pulsatile energy of the pressure wave, leaving low resistance organs like the brain vulnerable to microvascular mechanical damage. Due to access limitations, the effect of cerebrovascular stiffening on brain structure and neurological outcomes remains unknown. The purpose of this thesis was to assess the influence of vascular stiffening in peripheral arteries on white matter integrity (WMLv) (Chapter 2), obtain direct measures of cerebrovascular stiffness via phase contrast magnetic resonance imaging (PCMRI) (Chapter 3), and examine the impact …

Piezo1: Proteins For Mechanotransduction And Integration Of Endothelial Shear Stress & Intravascular Pressure, Juan Garcia Robledo M.D.

Electronic Thesis and Dissertation Repository

Piezo proteins are transmembrane ion channels, specialized in detecting mechanosensitive stimuli and transduce mechanical forces into biochemical signals. Piezo proteins research has helped understand physiological mechanisms, but the integrative role that Piezo1 plays in the regulation of the microvasculature has remained unstudied. Our main objective was to characterize ex vivo microvascular responses to the blockade of Piezo1 mechanotransduction in male (n=29) and female (n=24) Sprague-Dawley (SD) rats. Gracilis arterioles (GA) and middle cerebral arterioles (MCA) were harvested for ex-vivo vessel preparations. After vessel viability confirmation, every vessel was submitted to myogenic and flow challenges under control conditions and after Grammostola …

Assessing The Structure-Function Relationships Of The Apolipoprotein(A) Kringle Iv Sub-Type 10 Domain, Matthew J. Borrelli

Electronic Thesis and Dissertation Repository

Elevated plasma lipoprotein(a) (Lp(a)) is the most prevalent heritable risk factor in the development of cardiovascular disease. The apolipoprotein(a) (apo(a)) component of Lp(a) is strongly implicated in the pathogenicity of Lp(a). It is hypothesized that the inflammatory potential of Lp(a)/apo(a) is mediated by the lysine binding ability of the apo(a) kringle IV10 (KIV10) domain, along with its covalently bound oxidized phospholipid (oxPL). Using targeted mutagenesis, two novel null alleles for the LPA gene that generate non-secretable apo(a) species have been identified, resulting from amino acid substitutions in the KIV10 domain. A potential mechanism by which KIV10 oxPL modification is enriched …

The Effect Of Sepsis On Cerebral Microvascular Blood Flow, Laura Mawdsley, Mamadou Diop, Chris G. Ellis

Western Research Forum

Background: Sepsis is a dysregulated host response to infection that affects 18 000 000 people worldwide, and over 325 000 000 dollars are spent treating sepsis in Canada every year. One of the symptoms of severe sepsis is an altered mental state, which is accompanied with a measured decrease in oxygen levels in the skeletal muscle microvasculature. It is hypothesized that his altered mental state is due to a lack of oxygenated blood reaching the brain.

Hypothesis: After the onset of sepsis, microvascular cerebral blood flow and oxygen levels in the blood will decrease. Onset of decreased blood flow in …

The Purification Of Human Adult Progenitor Cell Types To Promote Angiogenesis, Stephen E. Sherman

Electronic Thesis and Dissertation Repository

Cellular transplantation strategies have aimed to combat critical limb ischemia (CLI) by inducing endogenous blood vessel regeneration. Transplantation of mesenchymal stromal cells (MSC) for CLI has proven safe and well-tolerated but demonstrated only modestly improved clinical outcomes explained in part by a lack of MSC survival and/or potency in ischemic tissues. This thesis focuses on the development of improved transplantation strategies for patients with CLI utilizing purified pro-angiogenic subsets of MSC and endothelial colony forming cells (ECFC) seeded within decellularized adipose tissue (DAT) bioscaffolds. First, I investigated whether purification of bone marrow-derived MSC based on a conserved stem cell function, …

Nicotinamide Riboside And The Aortic Response To Angiotensin Ii Infusion In Mice, Sina A. Ghoreishi

Electronic Thesis and Dissertation Repository

Damage to vascular cells of the aorta drives vascular dysfunction and disease. Nicotinamide adenine dinucleotide (NAD⁺) is a cellular metabolite critical to cellular health, but NAD⁺ levels decline during oxidative insults and aging. The NAD⁺ precursor, nicotinamide riboside (NR) can augment NAD⁺ levels. Herein, I determined whether orally administrated NR could protect the aorta of middle-aged mice from acute and sustained angiotensin II (Ang II) infusion-induced damage. I demonstrate that orally administered NR can protect the aorta from damage imposed by Ang II.

The Metalloproteinase-Dependent Role Of Timps In Regulation Of Pulmonary Microvascular Endothelial Cell Barrier Function During Sepsis, Marcello G. Masciantonio

Electronic Thesis and Dissertation Repository

Sepsis causes injury and dysfunction of pulmonary microvascular endothelial cells (PMVEC), leading to pulmonary edema. Metalloproteinases, are associated with inflammation and tissue damage, and their regulation by tissue inhibitors of metalloproteinases (TIMPs) may protect against septic PMVEC dysfunction. Thus, I hypothesize that murine septic PMVEC barrier dysfunction is due to disruption of the balance between metalloproteinases and TIMPs leading to increased metalloproteinase activity.

PMVEC were isolated from wild type (WT) and Timp3^-/- mice. Timp and metalloproteinase mRNA expression was altered under septic conditions and this was associated with increased metalloproteinase activity. Global metalloproteinase inhibitors BB-94 and TAPI-2 reduced albumin …

Automated Vascular Smooth Muscle Segmentation, Reconstruction, Classification And Simulation On Whole-Slide Histology, Yiwen Xu

Electronic Thesis and Dissertation Repository

Histology of the microvasculature depicts detailed characteristics relevant to tissue perfusion. One important histologic feature is the smooth muscle component of the microvessel wall, which is responsible for controlling vessel caliber. Abnormalities can cause disease and organ failure, as seen in hypertensive retinopathy, diabetic ischemia, Alzheimer’s disease and improper cardiovascular development. However, assessments of smooth muscle cell content are conventionally performed on selected fields of view on 2D sections, which may lead to measurement bias. We have developed a software platform for automated (1) 3D vascular reconstruction, (2) detection and segmentation of muscularized microvessels, (3) classification of vascular subtypes, and …

The Effects Of Intrauterine Growth Restriction (Iugr) On The Pulmonary Surfactant And Lung Injury, Reza Khazaee

Western Research Forum

The Effects of Intrauterine Growth Restriction (IUGR) on the Pulmonary Surfactant and Lung Injury

Khazaee R¹, McCaig LA², Hardy D¹, Yamashita CM², Veldhuizen, RAW²

Department of Physiology and Pharmacology¹, Western University, London, ON, Canada. Lawson Health Research Institute², London, ON, Canada

Background: Acute respiratory distress syndrome (ARDS) is defined as severe lung dysfunction that occurs after an insult to the lung such as an infection. The lung dysfunction in ARDS is due to alterations to surfactant, a lipid-protein mixture coats the inside of the lung and …

The Biophysical Alterations To Pulmonary Surfactant During Lung Injury, Scott D. Milos

Electronic Thesis and Dissertation Repository

Pulmonary surfactant is a lipoprotein mixture responsible for reducing surface tension of the lung. In this thesis, we investigate the impact of lung injury on surfactant composition and function, with a specific focus on cholesterol content. First, the impact of a high cholesterol diet on surfactant function was assessed in three models of lung injury. It was hypothesized that serum hypercholesterolemia would increase host susceptibility to surfactant functional impairments. Secondly, the impact of injurious ventilation on intracellular surfactant within the lung was investigated. It was hypothesized injurious ventilation would produce alterations to lamellar body surfactant. Overall, the data suggest that …

Effects Of Prenatal Exposure To Bisphenol A On Fetal Lung Development, Ayten Hijazi

Electronic Thesis and Dissertation Repository

Prenatal exposure to bisphenol A (BPA), one of the most prevalent endocrine disrupting chemicals, is associated with lung dysfunction and diseases in later life. However, it is unknown if this association has a fetal origin. In this thesis, a series of in vivo and in vitro experiments were conducted to determine the effects of prenatal exposure to BPA on fetal lung development, and define the underlying molecular mechanisms. Environmentally relevant doses of BPA were administered to pregnant mice via diet from embryonic day (E) 7.5 to 18.5. Fetal lungs were analyzed at E18.5 for changes in structure and expression of …

Gene Expression Microarray Data From Human Microvascular Endothelial Cells Supplemented With A Low Concentration Of Niacin, Nica M. Borradaile, Jennifer M. Hughes-Large

Physiology and Pharmacology Publications

The systemic lipid modifying drug, niacin, can directly improve human microvascular endothelial cell angiogenic function under lipotoxic conditions, possibly through activation of niacin receptors [1]. Here we provide accompanying data collected using Affymetrix GeneChip microarrays to identify changes in gene expression in human microvascular endothelial cells treated with 10 μM niacin. Statistical analyses of robust multi-array average (RMA) values revealed that only 16 genes exhibited greater than 1.3-fold differential expression. Of these 16, only 5 were identified protein coding genes, while 3 of the remaining 11 genes appeared to be small nuclear/nucleolar RNAs. Altered expression of EFCAB4B, …

Hyperpolarized 129xe Magnetic Resonance Imaging Of Radiation-Induced Lung Injury, Ozkan Doganay

Electronic Thesis and Dissertation Repository

Lung cancer is the largest contributor to cancer-related mortality worldwide. Only 20% of stage III non-small cell lung cancer patients survive after 5-years post radiation therapy (RT). Although RT is an important treatment modality for lung cancer, it is limited by Radiation-Induced Lung Injury (RILI). RILI develops in two phases: (i) the early phase (days-weeks) referred to radiation pneumonitis (RP), and (ii) the late phase (months). There is a strong interest in early detection of RP using imaging to improve outcomes of RT for lung cancer. This thesis describes a promising approach based on ¹²⁹Xe gas as a contrast …

Atrial Fibrillation Promotion By Intermittent Hypoxia In The Rat, Sara Bober

Electronic Thesis and Dissertation Repository

Obstructive sleep apnea (OSA) is a significant risk factor for developing atrial fibrillation (AF) in clinical populations, but the underlying mechanisms are unknown. Intermittent hypoxia (IH), as elicited by nocturnal airway obstructive events in OSA patients, has been implicated as the mediator of OSA-related cardiovascular outcomes. However, the role of IH in OSA-related atrial arrhythmogenesis has not been reported. For the first time, this thesis demonstrates AF promotion in a rodent model of OSA using IH to mimic hypoxic events, and investigates the underlying vulnerable substrates of induced AF. Rats exposed to IH for 7 days had significantly enhanced AF …

The Kinetics Of Cystatin C: A Marker For Dialysis Adequacy, Huang S. Shih-Han

Electronic Thesis and Dissertation Repository

When 90% or more of native kidney function is lost, renal replacement therapy must be initiated to sustain life. Renal transplantation is the preferred method, but availability is limited. The ideal dialysis prescription remains elusive. Small molecular weight molecules (such as urea and creatinine) have been used as markers of both kidney (native and transplant) and dialysis toxin clearance (function), but there are pitfalls in using these markers to assess total ‘renal’ dose (kidney plus dialysis). Body weight, gender and other factors also affect the concentrations of these small molecules, but not cystatin C. Furthermore, cystatin C has been shown …

Nicotinamide Riboside Delivery Generates Nad+ Reserves To Protect Vascular Cells Against Oxidative Damage, Krista M. Hawrylyshyn

Electronic Thesis and Dissertation Repository

The ability of vascular cells to withstand oxidative insults is critical to vascular health. NAD⁺, which drives poly (ADP-ribose) polymerase (PARP) and sirtuin (SIRT) reactions, can be compromised and strategies for overcoming this limitation in the vasculature do not exist. This study determines if nicotinamide riboside (NR) delivery can augment NAD⁺ stores and fuel resistance to oxidative stress. I established that oxidative-stress insult on vascular cells decreased NAD⁺ levels, accompanied by a striking increase in nuclear PAR-chain accumulation. PARP inhibition abolished PAR-chain formation and preserved NAD⁺ levels, establishing PARP in NAD⁺ consumption in this …

Novel Techniques For Investigating The Regulation Of Skeletal Muscle Hemodynamics, Baraa K. Al-Khazraji

Electronic Thesis and Dissertation Repository

The effect of the sympathetic nervous system (SNS) on blood flow distribution within skeletal muscle microvasculature is conditional upon regional activation of SNS receptors. Due to a lack of appropriate experimental models and techniques, no study has systematically evaluated the effect of SNS receptor activation in continuously branching skeletal muscle arteriolar trees. In line with previous work, we hypothesize that there will be a spatially-dependent distribution of sympathetic receptor activation along the arteriolar tree. Specifically, we anticipate a progressive decrease of adrenergic activation and a progressive increase of peptidergic and purinergic activation with increasing arteriolar order. We developed a novel …

Timp3 Regulation Of Macrophage Activation And Apoptosis, Michael S. Brock

Electronic Thesis and Dissertation Repository

Acute respiratory distress syndrome (ARDS) is a lung disease involving profound inflammation. Origins of persistent inflammation in select cases of ARDS are poorly understood, and we propose persistent inflammatory macrophages may be one of its mechanisms. Macrophages polarize to either promote inflammation, or suppress inflammation. Tissue inhibitor of metalloproteinases 3 (TIMP3) reduces the pro-inflammatory polarization in macrophages. Additionally, studies have shown TIMP3 promotes apoptosis, and its absence delays recovery from bleomycin-induced lung injury.

We hypothesize that TIMP3 promotes apoptosis of murine macrophages through inhibition of metalloproteinase activity and stabilization of FAS on the cell surface. Pro-inflammatory Timp3^-/- bone marrow-derived …

Surfactant And Matrix Metalloproteinase 3 In The Pathogenesis Of Acute Lung Injury, Valeria Puntorieri

Electronic Thesis and Dissertation Repository

Acute lung injury (ALI) is a pulmonary inflammatory disorder resulting in respiratory failure that is initiated by a number of different insults to the lung. Despite very high mortality, there are still no effective treatments for this disease, and the main supportive therapy, mechanical ventilation, can further lung injury and contribute to ALI progression. The overall objective of this work was therefore to evaluate the role of two key players in the disease process, such as: i) lung surfactant, a material essential for minimizing the work of breathing and for pulmonary immunomodulation, and ii) matrix metalloproteinase 3 (MMP-3), protease involved …

Pre-Diabetes And Sympathetic Nervous System Mediated Microvascular Dysregulation In Skeletal Muscle, Nicole M. Novielli

Electronic Thesis and Dissertation Repository

Pre-diabetes is associated with impairments in cardiovascular health that manifest prior to the onset of overt type 2 diabetes. Characterized by hyperinsulinemia and insulin resistance, pre-diabetes has been associated with increases in sympathetic nerve activity, which may result in augmented sympathetic control of the peripheral vasculature within skeletal muscle. Currently however, there are no studies investigating the impact of pre-diabetes on sympathetically-mediated vascular control. The primary study of this thesis investigated the effects of pre-diabetes on baseline sympathetic neuropeptide Y Y1 receptor (NPY Y1R) and alpha 1 adrenergic receptor (a1R) control of hindlimb vascular tone. Experiments were carried out in …

Cholesterol-Mediated Dysfunction Of Surfactant Effects Of Surfactant Protein-A And Diet-Induced Hypercholesterolemia, Joshua Qua Hiansen

Electronic Thesis and Dissertation Repository

This thesis explored the effects of cholesterol and SP-A on surfactant function in vitro, and lung function in vivo. In the first experiment, we determined whether SP-A could mitigate cholesterol-mediated surfactant dysfunction. We hypothesized that SP-A can mitigate the surfactant inhibition caused by high cholesterol. In the second experiment, we tested the contribution of diet-induced serum hypercholesterolemia to surfactant composition and the development of lung injury in rats. We hypothesized that serum hypercholesterolemia would increase the amount of cholesterol in surfactant and would cause rats to develop more severe lung injury. Our results indicate that SP-A mitigates cholesterol-mediated surfactant …

Adjustment Of Pulmonary O2 Uptake, Muscle Deoxygenation And Metabolism During Moderate-Intensity Exercise Transitions Initiated From Low And Elevated Baseline Metabolic Rates, Joshua P. Nederveen

Electronic Thesis and Dissertation Repository

When instantaneous step-wise transitions within the moderate intensity domain are initiated from elevated metabolic rates, the rate of pulmonary oxygen uptake (V̇O_2p) adjustment is slowed, and the V̇O_2p gain (ΔV̇O_2p /ΔWR) is greater. This study sought to determine the relationship between V̇O_2p kinetics and metabolic activity and energy status during step transitions from low and elevated metabolic rates within the moderate intensity domain. Ten young men completed six double-step constant load cycling bouts, consisting of step-wise transitions from 20 W to 45% θ_L and 45% θ_L [lower step (LS)] to 90% θ_{L …}

Characterizing Stomatin-Like Protein 2 And Its Role In Neuron Survival, Lisa A. Foris

Electronic Thesis and Dissertation Repository

Stomatin-like Protein 2 (SLP-2) has been identified as a stress-inducible transcript and has been shown to interact with and stabilize mitochondrial proteins. Since mitochondria are critical for neuronal function, we hypothesized that SLP-2 regulates neuron survival in response to stressful stimuli. A conditional SLP-2 knockout mouse (deletion) and the SN56 cell line (upregulation) were employed to study the role of SLP-2 in mitochondrial dynamics and neuron survival. SLP-2 deficient primary cortical neurons displayed significantly decreased levels of various mitochondrial respiratory chain proteins, indicating SLP-2 contributes to maintenance of mitochondrial membrane integrity. SLP-2 was up-regulated in response to oxidative stress and …