A myriad of factors contributes to the functional structural abnormalities in hypertensive arteries. Many reports have suggested a link between hypertension and insulin resistance and altered transport and metabolism of glucose, and none have assessed whether such alterations could contribute to the pathogenesis of vascular abnormalities in hypertension. We have recently determined that aortae from established DOCA-salt hypertension, a model without classical insulin resistance, have substantially lower poly- peptide levels of GLUT4, the insulin-responsive transporter, than doe aortae from Sham rats. Moreover, we found that altered glucose transporter expression and glucose uptake can lead directly to changes in intracellular Ca2+. Vascular contractility, MAP kinase signaling, apoptotic pathways, all of which could contribute to vascular abnormalities in hypertension. In addition, GLUT1, the major endothelial cell glucose transporter, has been shown to be the major transporter of ascorbate into endothelial cells. Therefore, our hypothesis is that alterations in vascular smooth muscle and endothelial cell glucose transporter expression occur during the development of hypertension, leading to changes in glucose and ascorbate uptake and metabolism. Altered glucose and ascorbate uptake and metabolism, in turn, can contribute directly to structural and functional arterial abnormalities characteristic of hypertension. 1. Complete the assessment of GLUT4 and GLUT1 expression and glucose uptake and metabolism in vascular cells in animal models of glucose transport abnormalities and hypertension. 2. Determine the effects of altered GLUT4 expression on blood pressure and endothelial-independent vascular contractility. 3. Determine the effects of altered GLUT4 expression on material morphology and apoptosis in murine models. 4. Determine the effects of altered GLUT4 expression cultured VSMC growth and death and MAPK and SAPK pathways. 5. Determine effects of GLUT1 expression on endothelial caveolar proteins, intracellular calcium, NO release, NOS activity. To test our hypothesis we will focus on a single model of hypertension in which major changes in vascular GLUT4 expression have been found, DOCA-salt hypertension. We will use this model to determine to what extent contractility and vascular morphologic changes of hypertension are due to altered glucose transporter expression. A major tool in this effort will be the study of animal models of altered GLUT4 expression, including GLUT4 (-/-) and (+/-) knockout mice, GLUT4 over-expressors, and potentially, mod4els in which GLUT1 expression is altered, and their responses to DOCA-salt hypertension.
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