UBC Theses and Dissertations
Atherosclerotic plaque ultrastructure following exposure of Watanabe heritable hyperlipidemic rabbits to particulate matter air pollution Tranfield, Erin M.
Epidemiological studies indicate that acute cardiovascular events follow exposure to particulate matter air pollution (PM₁₀) and preliminary animal studies have associated repeated PM₁₀ exposure with progressive changes in atherosclerotic plaques. The unexplored questions are those addressing the precise physiological and pathological cellular mechanisms that may account for the positive association between cardiopulmonary morbidity and mortality and PM₁₀ exposure. The overarching objective of these studies was to examine atherosclerotic plaques from rabbits exposed to PM₁₀ for morphological signs of remodelling and reorganization, with particular emphasis placed on the integrity of the endothelium and its underlying extracellular matrix; the cell population subtending the endothelium; and evidence of cap remodelling and destabilization. Watanabe heritable hyperlipidemic rabbits were exposed to 5 mg of urban PM₁₀ (EHC-93) (n = 8) or saline alone (n = 8) by instillation down the upper airways twice per week for four weeks. Following sacrifice, the abdominal aorta was processed for light and electron microscopy. Light microscopy and transmission electron microscopy qualitative and quantitative analyses were done on tissues processed for transmission electron microscopy. Samples were also processed for and analyzed using scanning electron microscopy. Light microscopy imaging revealed a significant accumulation of macrophage-derived foam cells immediately below the plaque endothelium of WHHL rabbits repeatedly exposed to PM₁₀ (p = 0.04). Qualitative electron microscopy observations showed an organizational change to the atherosclerotic plaques of PM₁₀ exposed WHHL rabbits evidenced by reduced plaque stratification, an absence of a distinct necrotic core and increased macrophage-derived foam cells subtending the endothelium. Using both 2- and 3-dimensional analyses, electron microscopy investigations demonstrated that the insinuation of macrophage-derived foam cells immediately below the endothelium of atherosclerotic caps of PM₁₀ exposed rabbits was associated with the separation of the endothelium from the reticulum of dense ECM (p < 0.0001), fragmentation of the reticulum of dense ECM and a significant increase in endothelial contact with macrophage-derived foam cells (p < 0.0039). Scanning electron microscopy analysis of plaques from control and PM₁₀ treated WHHL rabbits revealed intense leukocyte adhesion and emigration over the plaque core of the PM₁₀ exposed rabbits. As expected, leukocyte adhesion and transmigration were observed at the shoulder regions of atherosclerotic plaques from both control rabbits and PM₁₀ exposed rabbits and the surface morphology of the endothelium differed between the normal blood vessel wall and areas of atherosclerotic disease. PM₁₀ exposure promotes atherosclerotic plaque destabilization by the migration of macrophage-derived foam cells from the core of the atherosclerotic plaque, to the atherosclerotic cap regions and even into the systemic circulation. In the process of the migration, the reticulum of dense ECM subtending the endothelium is degraded compromising the stability of the endothelium over the atherosclerotic plaque cap.
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