Date of Award
Doctor of Philosophy (PhD)
Committee Member 1
Committee Member 2
Committee Member 3
An abdominal aortic aneurysm (AAA) is a localized expansion of the aorta. This disease can sometimes be caused by aortic dissections where the layers of the vessel wall separate, creating a false channel for blood to flow. AAAs are life-threatening because weakening of the vessel wall can lead to aortic rupture and internal bleeding. Unfortunately, most AAAs are associated with no signs or symptoms. Early diagnosis is therefore often not possible and recommendation for life-saving surgery could be delayed. As a result, the mortality rate for patients who experience aortic rupture is up to 90%. Currently we have an incomplete understanding of disease progression because aortic tissue is explanted only at a late stage of the disease. Hemodynamics and biomechanical forces on the vessel wall are thought to be important in development. These factors require further investigation with specific focus on the ongoing extracellular matrix remodeling and inflammatory processes. The overall goal of this work is to characterize the development of an established murine dissecting AAA model by integrating in vivo ultrasound with ex vivo molecular analyses. The novelty of this work is the longitudinal assessment of this model from early to late development and the utilization of advanced small animal imaging to identify pathology in vivo. Complex blood flow and vessel wall thrombus develop early and abruptly, likely influencing vascular growth and remodeling. In diseased animals, we measured significant volumetric growth of the suprarenal aorta, reflecting the large asymmetric expansion that is typically seen with this model. As well, a reduction in circumferential cyclic strain occurred in the suprarenal aortic wall,
indicating that the vessel wall became regionally stiffer. By histology, we observed characteristic features of the model, such as focal elastin breakage in the medial layer and collagen breakdown and remodeling in the adventitial layer. We also identified gene expression signatures for the early pathology that occurs in this model, including proinflammatory processes involving macrophages and neutrophils as well as vessel wall remodeling involving matrix metalloproteinases. The morphological, biomechanical, and hemodynamic changes in dissecting AAAs reflect both the microstructural changes and gene expression profile identified. Advanced ultrasound imaging to measure vessel strain and volume could help improve our prediction capabilities by identifying patients who are at greater risk for expansion and rupture. Additionally, a subset of identified biomarkers could serve as potential diagnostic or therapeutic targets that warrant further evaluation. Ultimately, we aim to help develop a means for accurate early diagnosis and treatment of human aortic disease.
Phillips, Evan H., "Imaging and molecular analysis of murine dissecting abdominal aortic aneurysms" (2018). Open Access Dissertations. 2048.