The central hypothesis to be examined in this proposal is that binding of modified lipoprotein to the CD36 receptor decreases the compliance of resistance vessels. Arteriole compliance can be modified by two mechanisms: 1) local endothelial-dependent vasodilation, and 2) central nervous system-dependent vasomotor tone. We propose that both mechanisms are physiologically significant and that both may participate in the development of atherosclerosis-dependent hypertension. Studies have been designed to test this hypothesis at the level of (1) individual molecules and cells (2) resistance vessels, and (3) whole animals. Furthermore, both local and central control mechanisms will be examined. The proposal consists of three Specific Aims. 1) To elucidate the molecular mechanisms responsible for CD36-dependent alterations in endothelial nitric oxide synthase function. This will be achieved by using human microvascular endothelial cells that express CD36. The effects of modified lipoproteins on caveola lipid composition, eNOS subcellular location, and eNOS post-secondary modifications will be determined. 2) To determine, in vivo and in vitro, the effect of modified lipoprotein-CD36 binding on resistance arteriolar responsiveness. The in vivo studies will use mesentery resistance arterioles. The in vitro studies will be accomplished by using isolated microcannulated resistance vessels from C57BL/6, CD36 null, apoE null, and CD36 x apoE null mice. The effects of modified lipoproteins on basal and agonist-induced endothelial nitric oxide synthase-mediated vasodilation will be assessed. In addition, the extent of calcium mobilization will be quantified. 3) To determine the extent to which modified lipoprotein-CD36 binding alters central nervous control of blood pressure in vivo. This will be accomplished by measuring SNA and blood pressure in C57BL/6, CD36 null, apoE null and CD36 x apoE null mice as a function of the degree of atherosclerosis. In addition, the ability of blood pressure to serve as a diagnostic tool for atherosclerosis and hypertension will be tested by relating alterations in SNA to the degree of lesion formation and elevations in blood pressure.
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