Interactions between hemodynamic forces and vascular permeability may be important in atherogenesis. The focal nature of atherosclerosis suggests that the fluid shear stress at the endothelial surface can influence the development of atherosclerotic lesions. The exact relationship between shear stress and atherogenesis and the effect of hemodynamic forces on endothelial permeability are poorly understood. The long term goals of this project are to develop an understanding of 1) the distribution of shear stress and permeability in arterial vessels susceptible to atherosclerosis; and 2) the mechanisms by which hemodynamic forces influence the vascular permeability and cellular metabolism of low density lipoprotein (LDL). The proposed research will examine: a) the rates of entry of LDL into the rabbit abdominal aorta at sites prone to the development of atherosclerotic lesions; b) the dependence of permeability upon the local hemodynamic environment; c) receptor-mediated and receptor-independent LDL accumulation and degradation in the arterial wall; and d) the relative importance of the various transport and metabolic processes. Permeability and metabolism will be examined by measuring concentration profiles of 125I-and 131I-tyramine-cellobiose-labeled LDL and methylated LDL using the technique of quantitative autoradiography. This technique permits resolution of areas as small as 100-500 mum2. Samples will be taken from sites around the renal and superior mesenteric arteries and the iliac bifurcation. Sites exposed to low and high shear will be examined. Vascular casts will be used to construct models of arteries. Flow studies will be conducted in vitro using these model vessels and shear stresses will be measured under physiological conditions using flush mounted hot film anemometry. Electron microscopy autoradiography will be used to localize the sites (intra-v. extracellular) of LDL and mLDL accumulation in the vessel wall. Results from these studies will permit integration of our understanding of the effect of hemodynamic forces on vascular permeability and metabolism of LDL. Mathematical model will incorporate two dimensional diffusion in the media and permit determination of the spatial variability of permeability and metabolism. In vitro studies will yield information on the distribution of shear stress in the same vessels in which transport studies will be performed. These results will be compared to determine the effect of shear stress on permeability. Finally, the results of this study will be correlated with the distribution of lesions in the rabbit abdominal aorta to examine the relationship between LDL permeability, shear stress and atherosclerosis.
