School of BioSciences - Theses

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    The effect of cardiovascular diseases on resistance vasculature and the efficacy of different treatments
    Kahlberg, Nicola Gayle ( 2019)
    Diabetes and hypertension are conditions that contribute to cardiovascular disease, which is a major cause of morbidity and mortality in the developed world. As the prevalence of obesity rises, the health burden will only increase. Vascular dysfunction, characterised by endothelial dysfunction and increased arterial stiffness, is a hallmark of cardiovascular disease and a major risk factor for the development of further cardiovascular events. Animal models are a necessary tool for diabetes research to elucidate disease pathologies and investigate potential treatment options. However, the precise disease pathology in different animal models of diabetes remains unknown. Further characterisation of vascular dysfunction in cardiovascular disease will help determine treatment options. Annexin-A1, an anti-inflammatory molecule that acts as a second messenger of the glucocorticoid pathway, has beneficial effects in diseases like diabetes, ischaemia-reperfusion injury and stroke. However, its effects on the vasculature remain unknown. The peptide hormone relaxin has shown some promise as a vasoprotective agent. My thesis first aimed to increase understanding of the pathogenesis of vascular disease in different animal models of diabetes. I then investigated the effects of annexin-A1 deficiency on the vasculature to determine the potential therapeutic role of annexin-A1. Finally, I explored the efficacy of relaxin treatment in a hypertensive model of vascular dysfunction. In Chapter 3, I describe the mesenteric vascular phenotype in moderate hyperglycaemia (20mM blood glucose) compared to severe hyperglycaemia (< 30mM blood glucose). While both models showed increased arterial stiffness, only severe hyperglycaemia caused endothelial dysfunction, indicating that arterial wall mechanics are more sensitive than endothelial function to increased blood glucose. Chapter 4 further investigated the effects of type 2 diabetes on the mesenteric vasculature. This study utilised a high fat diet with low dose STZ in mice to induce insulin resistance. Furthermore, this study characterised the effects of annexin-A1 deficiency on arterial remodelling in both insulin resistance and insulin deficiency. The main findings were that insulin resistance induced significant outward remodelling but had no effect on passive stiffness. Interestingly, insulin resistant annexin-A1 gene knockout mice had significantly increased vascular stiffness. Insulin deficiency induced outward remodelling and increased volume compliance in the mesenteric artery, regardless of genotype. Relaxin treatment reverses endothelial dysfunction in the mesenteric artery in hypertension and diabetes over a short treatment duration (<72 hours). However, the effect of a longer treatment duration in hypertension has not been investigated. Chapter 5 demonstrated that 10 days of continuous relaxin treatment reversed mesenteric artery endothelial dysfunction in hypertension by augmenting NO and EDH-mediated relaxation. Overall, my thesis further characterised the vascular phenotype in animal models of type 2 diabetes, which is important in understanding the disease process and for testing potential treatments. Additionally, I showed that both annexin-A1 and relaxin have the potential to be used as successful treatments in vascular dysfunction in the setting of diabetes and hypertension.