This investigation concerns the sequence of events leading to the formation and localization of early atherosclerotic lesions. The long-term objectives are to determine the inter-relationship among lipoprotein accumulation and oxidation, intimal accumulation of macrophages, and arterial fluid mechanics during the initial stages of atherosclerosis. Three hypotheses will be tested: 1) Antioxidants reduce the rate of monocyte entry into the vessel wall but do not affect LDL oxidation and monocyte and LDL residence times; (2) Antioxidants alter the number of adhesion molecules present on the endothelium in lesion-prone areas; (3) The rate of monocyte entry into the vessel wall represents the interaction among cells in the luminal flow, the presence of secondary flows which transport monocytes to the endothelium, adhesion molecule expression, and local mass transport of chemotactic agents released by the endothelium and intimal macrophages. Three approaches will be used: fluorescently labeled monocytes to study monocyte transport into, and macrophage accumulation within, the intima; quantification of adhesion molecule densities; and computational fluid dynamics. These approaches will allow examination of the dynamics of macrophage accumulation, the relationship between monocyte adhesion and adhesion molecule density, the role of normal and oxidized LDL upon adhesion molecule expression and macrophage accumulation, and the influence of hemodynamics on adhesion molecule expression and monocyte adhesion.
Specific Aims are as follows: 1) Determine the effect of antioxidants on macrophage dynamics and LDL residence times at lesion-prone sites during early atherogenesis, (2) evaluate the role of oxidized LDL upon adhesion molecule density and macrophage entry into the vessel wall, (3) examine the relationship between three-dimensional numerical simulations and measurements of adhesion molecule density and monocyte adhesion and accumulation. Results from these experiments will more clearly define the sequence of events occurring during atherogenesis and the contribution of normal and modified LDL to lesion initiation.
| Buchanan, J R; Kleinstreuer, C; Hyun, S et al. (2003) Hemodynamics simulation and identification of susceptible sites of atherosclerotic lesion formation in a model abdominal aorta. J Biomech 36:1185-96 |
| Ogunrinade, Olakunle; Kameya, Geri T; Truskey, George A (2002) Effect of fluid shear stress on the permeability of the arterial endothelium. Ann Biomed Eng 30:430-46 |
