Cardiovascular complications are the leading causes of morbidity and mortality in individuals with obesity, type 2 diabetes mellitus (T2DM), and insulin resistance. Complications include pathologies specific to large (atherosclerosis, cardiomyopathy) and small (retinopathy, nephropathy, neuropathy) blood vessels. Common among all of these diseases is an altered endothelial cell phenotype (i.e., endothelial cell dysfunction) that is characterized by reduced nitric oxide (NO) bioavailability. Understanding the mechanisms linking obesity and dyslipidemia to the impairment in endothelial function is essential for developing new therapeutic strategies to combat these debilitating disorders. The persistent exposure of blood vessels to elevated fatty acids and lipoproteins leads to the aberrant production of ceramides, a class of sphingolipids that inhibit NO production. Interventional studies in rodents have shown that pharmacological and genetic approaches that inhibit enzymes required for ceramide synthesis systemically prevents endothelial dysfunction, ameliorates systemic hypertension, and lessens the development of atherosclerosis. These data suggest strongly that vascular ceramides are important drivers of the endothelial dysfunction that underlies cardiovascular disease. The specific contribution from endothelial cell ceramide accumulation or depletion to vascular dysfunction, until now, has been impossible to determine. This is important to quantify because ceramide synthesis inhibitors are being developed for therapeutic applications, and precise targets are desired in an effort to minimize unwanted side-effects. Our group has generated novel murine models that allow for tamoxifen inducible, endothelial cell specific ceramide accumulation or depletion. In Aim 1 we will test the hypothesis that endothelial cell-specific ceramide accumulation evokes cardiovascular dysfunction in lean mice. In Aim 2 we will test the hypothesis that endothelial cell-specific ceramide biosynthesis inhibition attenuates cardiovascular dysfunction that otherwise develops in obese mice. Discoveries that will be made by completing the described experiments have strong potential to move the field of sphingolipid signaling and vascular function forward in a manner that is not incremental.
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