Individuals with diabetes mellitus often develop complications that traditionally have been separated into microvascular pathologies, such as retinopathy, nephropathy and neuropathy, or macrovascular pathologies, including cardiovascular disease. Increasing evidence suggests that these micro- and macro-vascular complications may be linked. Our objective is to determine if direct effects of hyperglycemia on a microvascular bed that supplies cells in large arteries, the vasa vasorum, promotes diabetes-associated accelerated atherosclerosis.
Normoglycemic apolipoprotein-E deficient (ApoE-/-) mice showed continuous atherosclerosis progression throughout the study that was directly correlated to increased vasa vasorum density with time. Hyperglycemic ApoE-/- Ins2+/Akita mice and streptozotocin-injected (STZ) ApoE-/- mice also demonstrated progressive plaque growth over time, but had accelerated atherosclerosis at 15 weeks of age compared to normoglycemic controls. The increased
atherosclerosis in hyperglycemic mice correlated with impaired angiogenesis at 10 and 15 weeks of age. These mice showed increased expression for a marker of hypoxia in the atherosclerotic lesions yet decreased expression of vascular endothelial growth factor (VEGF), suggesting disruption of hypoxia-mediated angiogenesis. Cell culture experiments suggested that alternative splicing of an antiangiogenic form of VEGF in macrophages as well as post-translational modifications of macrophages and smooth muscle cells may contribute to
reduced VEGF expression and decreased vasa vasorum neovascularization. After 25 weeks of age, vasa vasorum expansion plateaued in normoglycemic mice but continued to increase in hyperglycemic ApoE-/- STZ-injected mice. The increase in vasa vasorum neovascularization correlates to increases in plasma cholesterol.
We have shown that hyperglycemia alters the microvascular structure of the vasa vasorum in two distinct mouse models of diabetes. Initially, elevations in glucose correlate to a significant reduction in lesion vascularization that results in increased lesional hypoxia that may promote the development and progression of atherosclerosis. At later time points there appears to be a burst of neovascularization that correlate with increases in cholesterol. / Thesis / Master of Science (MSc) / People with diabetes have elevated glucose levels that affect the vessels that distribute blood in our body. This puts them at higher risk of developing cardiovascular disease and having heart attacks and strokes. One set of vessels, known as the vasa vasorum, delivers blood to the walls of larger vessels. The primary goals of this study are 1) to determine if diabetes affects the vasa vasorum and, 2) to determine if changes to the vasa vasorum increase a person’s risk of developing cardiovascular disease. The results of this study show that diabetes in mice decreases the number of vasa vasorum vessels. The decrease in vasa vasorum blood vessels appears to influence the larger blood vessels they supply which promotes an environment that is more prone to cardiovascular disease. This information could be used in the future to develop drugs that target the vasa vasorum and possibly decrease cardiovascular events.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/18158 |
| Date | January 2015 |
| Creators | Stoute, Heidi |
| Contributors | Werstuck, Geoff, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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