Atherogenesis is a complex process that appears to be initiated by alterations of endothelium. An elevated level of plasma low-density lipoproteins (LDL) is thought to be responsible for the development of atherosclerosis because the characteristics of LDL-induced endothelium dysfunction are very similar to those observed in hypercholesterolemic and atherosclerotic subjects. Indeed, exposure of normal large coronary arteries to pathological concentrations of LDL inhibits endothelium- dependent vasorelaxation within minutes. However, it is unclear whether coronary microvessels (<150 MU m) are also susceptible to LDL. This issue is important because these microvessels not only contribute over 70% of coronary resistance but also play a major role in the regulation of coronary blood flow. Interestingly, many studies have shown that administration of a high dose of L-arginine normalizes atherosclerosis- and LDL-induced vascular dysfunction. Since L-arginine is a biological precursor for nitric oxide (NO) synthesis, these results may suggest that the observed vascular dysfunction is due to the impairment of NO synthesis and/or release during LDL exposure. However, the underlying mechanism responsible for this impairment has not been identified, especially at the microcirculatory level. In addition, the mechanism of restoring vascular function by L-arginine is also unclear. Therefore, it is hypothesized in this proposal that the elevated LDL, especially oxidized LDL, alters L- arginine transport and/or L-arginine/NO metabolism in the endothelium and thus leads to vascular dysfunction due to the impairment of NO synthesis and/or release. To test this hypothesis, the experiments are designed: I) to demonstrate conclusively that the deficiency in endothelial release of NO during LDL exposure is responsible for the vascular dysfunction, 2) to determine the alterations of L-arginine transport and metabolism toward the synthesis of NO during LDL exposure, and 3) to delineate the mechanism(s) of restoring vascular function by the administration of L-arginine. To achieve these goals, we will use both isolated arterioles (<150 MU m) and cultured endothelial cells from the porcine coronary microcirculation as experimental models. The isolated arterioles will be cannulated and pressurized for functional study. The cultured cells will be used to probe the mechanism of alteration of L-arginine/NO metabolism. The intact vessel and cultured cell studies will complement each other to address the relationship between vascular function and endothelial L-arginine/NO metabolism during exposure to atherogenic agents. Results from these studies will provide valuable information toward our understanding of the mechanism of vascular dysfunction during the development of atherosclerosis. In addition, elucidation of anti-atherogenic effect of L- arginine may provide a foundation for future therapeutic manipulation of vascular function during hypercholesterolemia and/or atherosclerosis.
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