In this proposal, a new hypothesis is advanced for the local origin of atherogenesis which attempts to relate local changes in macromolecular permeability to the detailed sequence of events and mechanisms leading to the formation of the foam cell lesion. The hypothesis offers a possible explanation for the relationship between arterial wall cell turnover, macromolecular permeability, the receptor mediated metabolism of the cellular component of the arterial intima and media, the recruitment and subendothelial penetration and transport of blood borne monocytes and their conversion to macrophage type foam cells. The time dependent model developed by the principal investigators to show the quantitative relationship between endothelial macromolecular permeability and leaky junctions associated with statistically infrequent cells in turnover will be further developed to include: (1) a discrete diffusion barrier for the internal elastic lamina, (2) convection in the interendothelial clefts and subendothelial tissue and (3) models for the receptor mediated low density lipoprotein (LDL) metabolism of the endothelial and smooth muscle cells. The quantitative models in (3) will be based on the experimental model of Brown and Goldstein for the LDL receptor mediated metabolism and the intracellular regulation of their number density in human fibroblasts. Simplified mathematical models have been formulated for the six key processes governing this regulation wherein the constants in the individual processes are determined from available experiments. The objective of these models is to obtain a quantitative predictive relationship between the extracellular native LDL concentration, the hydrolyzed free cholesterol content of the cells and the regulation of receptor number. The subendothelial LDL concentration predicted by the overall model is then related to the release of chemotactic factors for the recruitment and adhesion of blood borne monocytes based on the quantitative criteria proposed in the new hypothesis. Experiments conducted in a complementary NIH grant have recently confirmed the first part of the hypothesis showing that the leakage of LDL across the endothelium does occur via poorly formed junctions surrounding the small population of cells in turnover. Further experiments are required to validate the quantitative link between subendothelial LDL levels and monocyte recruitment proposed in the new hypothesis.
