Doctor of Philosophy (PhD)
Pathology & Microbiology
B. Timothy Baxter
Abdominal aortic aneurysm (AAA) is a dynamic vascular disease characterized by inflammatory cell invasion and extracellular matrix (ECM) degradation. Evidence has demonstrated a profound influence of genetic background on AAA formation. The work presented herein discusses two studies: the first demonstrates how genetic components can enhance the susceptibility to AAA formation and the second demonstrates how ECM degradation enhances AAA progression by influencing inflammatory cell phenotypes. An understanding of the pathways involved in AAA pathogenesis can help not only to identify potential patients at risk of AAA development, a heritable disease in which the incriminating component has yet to be discovered, but also to identify therapeutic targets for medical therapy. By using the CaCl2 model of aneurysm formation, we were able to induce aneurysms in two different strains of mice, C57Bl/6 and 129/SvEv. While both strains developed aneurysms, 129/SvEv mice developed larger aneurysms, increased inflammatory cell infiltration, and had higher MMP expression compared to C57Bl/6 mice. We believe this increased susceptibility is due to increased ProMMP-2 expression at baseline. This increase in MMP expression may help to explain why some patients develop aneurysms at faster rates than others or why some patients may be predisposed to aneurysm formation while others form atherosclerotic plaque.
Furthermore, our study examines how products released from damage to the aortic wall, particularly the breakdown of elastin and the release of elastin-derived peptides (EDPs), influence the surrounding microenvironment. Pro-inflammatory M1 macrophages initially are recruited to sites of injury but, if their effects are prolonged, can lead to chronic inflammation that prevents normal tissue repair. The EDPs released from aortic wall damage create a pro-inflammatory M1 macrophage phenotype. By using CaCl2 to induce AAA formation, we show how manipulation of this pro-inflammatory response by direct injection of anti-inflammatory M2 macrophages can reduce aortic dilation. Antibody-mediated neutralization of EDPs can attenuate aortic dilation by preventing macrophage recruitment to the damaged aortic wall, reducing MMP upregulation, and influencing the M1/M2 phenotype ratio. By manipulating the M1/M2 ratio, we identify a potential therapeutic target in the fight to discover a medical therapy and minimize the need for invasive mechanical intervention in AAA.
Dale, Matthew A., "Genetic Predisposition and M1 Macrophage Polarization Created by Elastin-Derived Peptides Drive Abdominal Aortic Aneurysm Formation" (2016). Theses & Dissertations. 83.