Investigating the Pro-Atherogenic Potential of Chronic Hyperglycemia: Is Diabetic Atherosclerosis a Microvascular Complication?

Abstract

<p>Diabetes mellitus (DM) is associated with a significantly increased risk of microvascular complications, such as retinopathy, nephropathy, and neuropathy, as well as macrovascular disorders, including cerebro- and cardiovascular disease. Traditionally, the micro- and macro- vascular complications of DM have been considered distinct and independent disorders; however, data from several epidemiological and pathophysiological studies suggest they may be linked. It has been suggested that the <em>vasa vasorum</em>, a microvascular network which nourishes the walls of large muscular arteries, may play a role in macrovascular atherosclerosis. The effect of hyperglycemia on the microvessels of the vasa vasorum, and the potential impact of these effects on macrovascular atherosclerosis are not known.</p> <p>Here, we use a multiple-low-dose streptozotocin (STZ) injected apolipoprotein-E deficient mouse model to investigate the effects of hyperglycemia on the vasa vasorum, and to correlate such effects to atherosclerotic plaque progression. Hyperglycemia significantly increased plaque size and necrotic area (3- and 4-fold, respectively) relative to controls by 15 weeks of age. However, the density of vasa vasorum microvessels in the aortic wall of hyperglycemic mice was reduced at each time point examined. A similar vasa vasorum deficiency was also seen in STZ-induced hyperglycemic C57Bl/6J mice and hyperglycemic Ins2^Akita mice, and microvessel density could be corrected by insulin-mediated glucose normalization, suggesting a hyperglycema-specific effect. A localized deficiency in VEGF appears to be responsible for the reduced neovascularisation. Lastly, hyperglycemic mice fed standard chow supplemented with benfotiamine, a drug used to treat microvascular disorders in DM, appear to have reduced atherosclerosis.</p> <p>These findings provide the first indication that, in addition to retinal and glomerular capillary beds, hyperglycemia alters the microvessel structure of the vasa vasorum. Such microvascular changes directly correlate to the development and progression of atherosclerosis in hyperglycemic ApoE-deficient mice.</p>