INVESTIGATING THE EFFECTS OF HYPERGLYCEMIA ON THE VASA VASORUM IN THE DEVELOPMENT OF ATHEROSCLEROSIS AND ESTABLISHMENT OF NOVEL MOUSE MODELS OF DIABETES

Abstract

The prevalence of diabetes is increasing rapidly around the world. People with diabetes are 2–4 times more likely to die from cerebro and cardio-vascular causes than people with no history of diabetes, even after controlling for other risk factors. Atherosclerosis, the underlying cause of most cardiovascular disease (CVD), is accelerated in people with diabetes, but several clinical trials have questioned the efficacy of glucose lowering therapies. A better understanding of the molecular pathways by which diabetes accelerates atherosclerosis will expand the scope of current targets and strategies for more effective therapies. In this thesis we investigate a novel mechanism and establish and characterize new hyperglycemic mouse models for the study of diabetic atherosclerosis. Firstly, we investigate the effects of hyperglycemia on the vasa vasorum, the microvascular network that surrounds and supplies large vessels, and correlate those effects to the development of atherosclerosis. In normoglycemic ApoE-/- mice, the vasa vasorum expands as atherosclerotic lesions grow. However, in hyperglycemic ApoE-/- mice there is no significant neovascularization of the vasa vasorum despite the enhanced atherosclerotic development. We hypothesize that the ability of hyperglycemia to disrupt vasa vasorum neovascularization may promote the development and progression of atherosclerosis in diabetes. Secondly, we establish, characterize and manipulate a new model of hyperglycemia-induced atherosclerosis: the ApoE-/-:Ins2+/Akita mouse. We describe sex-specific differences of the ApoE-/-:Ins2+/Akita mouse model. Male ApoE-/-:Ins2+/Akita mice develop chronic hyperglycemia and accelerated atherosclerosis. Castration slows atherosclerosis in ApoE-/-:Ins2+/Akita mice but enhances it in normoglycemic controls. Female ApoE-/-:Ins2+/Akita mice are only transiently hyperglycemic but still present with accelerated atherosclerosis. Ovariectomized ApoE-/-:Ins2+/Akita mice are chronically hyperglycemic and show indications of advanced atherosclerosis. Lastly, we investigate the effects of a western-type diet on the hyperglycemic ApoE-/-:Ins2+/Akita mice. We demonstrate the pernicious phenotype of the mice leading to a significantly shortened lifespan correlated with massive atherosclerosis that extends to the aortic sinus, ascending and descending aorta, brachiocephalic artery and coronary arteries. In conclusion we provide insights for a new mechanism by which hyperglycemia may accelerate atherosclerosis and possible role of the vasa vasorum in the progression of atherosclerosis in hyperglycemic mice. We also establish new mouse models that illuminate the action of sex hormones on pancreatic beta-cell function and the vasculature. These models will provide a test bed to further study sex hormone effects, as well as the diabetic pathways that promote atherosclerosis.