The role of oxidative stress in abdominal aortic aneurysm development: molecular and mechanical effects in the origins of aneurysmal disease

The etiology of abdominal aortic aneurysms (AAA) is characterized by localized extracellular matrix remodeling and vessel dilation. Population-based studies have shown that AAA account for nearly 1% of all deaths. This thesis seeks to identify the earliest molecular and biomechanical determinants of aneurysm formation. Our initial motivator was the lack of information defining the underlying mechanisms of AAA formation. We used isolated vessel testing and histological analysis to study the mechanical and morphological evolution of AAA. These factors were measured in murine models of reproducible AAA formation. From this study, we determined 1) that molecular events precede mechanical events in AAA progression and 2) aortic circumferential mechanics are well conserved during AAA pathogenesis. Next we sought to explore the mechanistic link between oxidative stress and AAA development. To determine this relationship we used isolated vessel testing as well as measurement of aortic residual circumferential strain. To isolate the role of oxidative stress in these studies we used a line of transgenic mice with vascular smooth muscle cell-specific overexpression of the antioxidant catalase. The results of this study suggest that oxidative stress-mediated elastin degeneration within the aortic media is etiologic of altered aortic mechanics. Lastly, we sought to determine the independent mechanical contribution of the aortic adventitia and media tunica to overall aortic behavior. To accomplish this goal we compared the circumferential and axial mechanical behavior of aortas with and without collagenase treatment. The data demonstrated that the adventitia regulates the circumferential behavior of the aorta by preventing overstretch and the media regulates the axial behavior by maintaining tensile loading. This thesis demonstrates 1) that detecting early aneurysm progression in the form of mechanical or geometric changes may miss the window in which aneurysm pathology may be potentially reversed, 2) that mitigating oxidative stress within the aortic wall may provide protection against AAA, and 3) the adventitia is an important load bearing constituent of the arterial wall and plays a role in vascular adaptation to altered mechanical states. Overall our results impact understanding of early aneurysmal pathogenesis and may facilitate the development of preventative therapies for AAA progression and rupture.Ph.D.Committee Chair: W. Robert Taylor; Committee Member: John Oshinski; Committee Member: Kathy Griendling; Committee Member: Raymond P. Vito; Committee Member: Rudolph L. Gleaso