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Large vessel vasculitis (LVV), including giant cell arteritis (GCA) and Takayasu arteritis (TAK), is the most common form of primary vasculitis and is characterised by chronic inflammation of medium and large arteries. Accurately determining disease activity in LVV is challenging, particularly once treatment has started. This often leads to a mismatch between disease activity and treatment intensity leaving patients at risk of the consequences of over-treatment, including adverse effects of toxic therapies, or under-treatment, leading to unchecked vascular inflammation and arterial damage. The aim of this thesis was to develop novel methods of assessing disease activity in order to better guide treatment for patients with LVV. The results presented here demonstrate that hybrid positron emission tomography with magnetic resonance imaging (PET/MR) is able to accurately distinguish active from inactive LVV and can track disease activity longitudinally. MR metrics provide complementary information to that provided by PET metrics for determination of disease activity status. A novel, PET/MR-specific disease activity assessment score - the VAMP score - appears more effective at distinguishing active from inactive LVV than established PET-only scoring systems. The imaging data provided by PET/MR have the potential to positively influence 'real-world' clinical decision making. Considering that PET/MR utilises a significantly lower radiation dose compared with PET/CT, these results support the use of PET/MR for longitudinal disease monitoring in LVV. This thesis has also demonstrated the efficacy of a series of new and emerging serological biomarkers of disease activity in LVV. Plasma concentrations of leucine-rich alpha-2- glycoprotein-1 (LRG1), angiopoietin-2 (Ang-2), soluble fms-like tyrosine kinase-1 (sFlt-1), osteopontin, and calprotectin are elevated in LVV compared with health. Additionally, LRG1, Ang-2 and osteopontin can distinguish active LVV from inactive LVV, with all biomarkers outperforming C-reactive protein (CRP) for this indication. Correlations were observed between several of the evaluated biomarkers and previously defined measures of disease activity. Finally, I have demonstrated the ability of microcirculatory changes to inform LVV disease activity based on examination of retinal microstructures using optical coherence tomography (OCT). Patients with LVV exhibit chorioretinal thinning which is reversible with treatment. Correlations were also observed between OCT metrics and both PET/MR-based and serological measures of disease activity. These results suggest that microcirculatory dysfunction plays a role in the development and maintenance of inflammation in LVV and may be amenable to therapeutic targeting. Additionally, consideration should be given to the eye as a window through which to define and track disease activity in LVV. In summary, this thesis has identified several ways in which monitoring of disease activity in LVV might be improved. These findings have the potential to enhance LVV patient care by facilitating more accurate matching of treatment intensity with disease activity. Larger, multi- centre studies are now required to confirm and expand on these findings.

Fluctuation in tissue oxygen tension results in systemic physiological, metabolic, and vascular changes in order to maintain cellular homeostasis. Using C57BL/6J mice exposed to normoxia, hypoxia or hyperoxia, we studied the systemic physiological and brain microvascular adaptive changes in response to fluctuations in atmospheric oxygen level. In the first part of this project, we determined the relative time course of capillary angiogenesis and regression including expression of some of the signaling factors involved in the process during chronic hypoxia and subsequent re-oxygenation. Results indicated that expressions of hypoxia inducible factor-1¿¿ (HIF-1¿¿), vascular endothelial growth factor (VEGF) and erythropoietin (EPO) were increased during hypoxic exposure and diminished during subsequent re-oxygenation. However, expressions of cyclooxygenase-2 (COX-2) and angiopoietin-2 (Ang-2) were elevated during hypoxia as well as re-oxygenation. Significantly increased capillary density at the end of the 3rd week of hypoxia regressed back toward normoxic baseline during re-oxygenation.In the second part of this study, we analyzed adaptive changes during chronic hyperoxia. Results showed accumulation of HIF-1 and 2¿¿, and increased expression of EPO, COX-2 and Ang-2. Conversely, VEGF, and VEGF receptor-2, PPAR-¿¿¿ coactivator (PGC-1¿¿) and prolylhydroxylase domain-2 (PHD-2) expressions were decreased. VEGF mRNA level was diminished but there was no change in HIF-1¿¿ mRNA and von Hippel Lindau (VHL) protein expression during hyperoxia, with capillary density significantly diminished by the 3rd week of hyperoxia. In the third part of the study, we analyzed whether aging affects systemic and cerebral angiogenic adaptive changes in response to prolonged hypoxia in the mouse. Our data showed that during hypoxia, accumulation of HIF-1¿¿ was attenuated, and VEGF expression was decreased in the cerebral cortex of aged mice. Conversely, COX-2, Ang-2, and PGC-1¿¿ protein upregulation were not affected in the aged cohort. Despite an initial delay in cerebral angiogenic response in aged mice, no significant differences were observed in the capillary density between the young and aged mice cerebral cortex in normoxia and throughout the 2nd and 3rd weeks of hypoxia. Overall, we can conclude that the brain capillary density is a continuously adjusted variable with tissue oxygen availability as a critical controlling modulator.