Rationale. Cigarette smoking is a well-known risk factor for cardiovascular disease, including arterial diseases such as atherosclerosis and abdominal aortic aneurysm. However, our understanding of how exposure to cigarette smoke impacts arterial disease pathogenesis is not well known. Consequently, this doctoral thesis focuses on understanding the development of atherosclerosis and aortic aneurysm in the context of exposure to cigarette smoke. In particular, since monocytes and macrophage are key immune cells implicated in arterial pathology, this work concentrates on understanding the impact of cigarette smoke exposure on the function and kinetics of monocytes and arterial macrophages.
Main Findings. Using a mouse model that combines two clinically relevant risk factors, hyperlipidemia and cigarette smoke, we showed that smoke exposure increases atherosclerosis and induces the spontaneous formation, progression, and rupture of abdominal aneurysms. We also provide experimental evidence that atherosclerosis strongly associates with regions of elastin damage and arterial dilation, suggesting atherogenesis may directly contribute to abdominal aneurysm formation.
Given the importance of macrophages in arterial disease, we investigated arterial macrophage heterogeneity and function following exposure to cigarette smoke. We report that cigarette smoke exposure increased the abundance of arterial monocytes and macrophages, whereas heterogeneity was primarily driven by hypercholesterolemia in aneurysmal tissue. Specifically, hypercholesterolemia is associated with an increase in macrophage populations with putative functions in inflammation and tissue remodelling including Trem2 foamy macrophages, inflammatory macrophages, and interferon-inducible macrophages. Moreover, we demonstrated that arterial macrophages play a critical role in elastin fragmentation within the arterial wall of smoke exposed mice.
Finally, we investigated the impact of cigarette smoke on kinetic factors that can contribute to arterial macrophage accumulation. We found that, despite increased development of arterial disease, exposure to cigarette smoke is associated with an overall suppression of circulating monocytes and pro-inflammatory cytokines. Using a parabiosis model, we show monocyte recruitment is significantly increased and is likely a key factor contributing to accumulation of arterial macrophages following exposure to cigarette smoke. We also present evidence suggesting that endothelial dysfunction, related to a loss of endothelial nitric oxide synthase, contributes to increased arterial monocyte recruitment following exposure to cigarette smoke.
Conclusions and Significance. Overall, we provide evidence that atherosclerosis likely contributes to abdominal aneurysm pathology in a model of cigarette smoke-induced aneurysm formation. We further provide insight into how tobacco smoke promotes arterial disease development through increased local accumulation of arterial macrophages despite suppressed monopoiesis and systemic inflammation. We identify monocyte recruitment and endothelial dysfunction as key factors contributing to the increased accumulation of arterial macrophages, with no overall differences in macrophage heterogeneity, following smoke exposure. In addition to providing insight into the increased risk of arterial disease following exposure to cigarette smoke, this study also provides experimental evidence that atherogenesis can contribute to abdominal aneurysm pathology. Overall, this thesis furthers our understanding of arterial disease pathogenesis and can provide a foundation for further mechanistic or therapeutic focused research aimed at reducing the burden of cardiovascular disease. / Thesis / Doctor of Philosophy (PhD) / Diseases that affect the heart and major blood vessels are one of the leading causes of illness and death worldwide. Atherosclerosis is one such disease caused by the buildup of fatty deposits in the walls of major blood vessels called arteries. This buildup can eventually block the artery and lead to a heart attack or stroke. Abdominal aortic aneurysms are another type of disease that affects arteries. In this case, the walls of the artery grow weak and begin to balloon out until the artery eventually breaks causing severe internal bleeding and death. One of the most important cells involved in the development of atherosclerosis and aneurysms is the macrophage, a type of white blood cell that is an important part of the immune system and found in diseased arteries. Although we know that cigarette smoking is one of the most significant risk factors for developing atherosclerosis and abdominal aneurysms, we do not fully understand why. Therefore, the goal of this thesis project was to investigate how cigarette smoke affects the development of arterial disease with a focus on understanding how it impacts the movement and function of macrophages. Using a mouse model, we found that the development of atherosclerosis and aneurysm are likely related, and also identified ways that exposure to cigarette smoke increases the numbers of macrophages in arteries. This work advances our understanding of how arterial diseases may be related and provides insight into how smoking can increase the risk of developing arterial disease.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/26710 |
| Date | January 2021 |
| Creators | Thayaparan, Dharneya |
| Contributors | Stampfli, Martin, Medical Sciences (Molecular Virology and Immunology Program) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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