Comparative Structural Biology Of The Aorta And Implications For Aneurysm Formation

An aortic aneurysm describes the irreversible degradation and dilation of the aorta. This can occur at many sites along the aorta but does so with varying frequency. A key clinical finding is the frequent observation of abdominal aortic aneurysms (AAAs) in comparison to those of the external iliac artery (EIA), which forms much later in embryogenesis, where they are seldom seen. This work tested the overall hypothesis that there is a fundamental difference in the structure of the aorta that influences a predisposition to aneurysmal disease. For this, tissue was collected from 16 aortic sites. Immunohistochemistry was used to quantify collagen and elastin; the percentage of both were similar from aortic root to the level of the renal arteries. From the renal arteries to the EIA, the percentage of collagen increases and was significantly higher than the percentage of elastin. Scanning electron microscopy investigated the collagen microstructure and identified that the mean collagen fibre diameter within the EIA wall was significantly larger than at the abdominal aorta. Finally, proteomic analysis identified proteins that could be taken forward for further analysis. These were quantified along the length of the aorta using IHC, to determine whether they may influence aneurysmal degradation. Difficulties in obtaining aortic wall samples meant other investigations were simultaneously pursued. Further work in this thesis aimed to identify biomarkers associated with increased AAA growth rate. This work used both Enzyme-linked immunosorbent assays (ELISAs) and metabolomics for the analysis of plasma from AAA patients. No significant association was found using the ELISAs, but metabolites putatively associated with increased AAA growth were identified using metabolomics. Finally, the association between low-density lipoprotein receptorrelated protein 1 (LRP1) and AAAs was investigated. The final part of work in this thesis aimed to quantify LRP1 activity and successfully developed two transient LRP1 knockdown models.