INFLAMMATORY MECHANISMS OF ATHEROMA FORMATION - INFLUENCE OF FLUID-MECHANICS AND LIPID-DERIVED INFLAMMATORY MEDIATORS

It has been suggested that atheroma formation is a chronic inflammator y response to lipid-derived inflammatory mediators accumulating at sel ected arterial sites. At large artery flow dividers and curvatures, se condary flow phenomena create zones of stagnation and recirculation th at deprive endothelial cells of shear stress-induced differentiation. Endothelial cell phenotypes at these sites appear to represent activat ed cells expressing membrane-associated and secreted molecules that fa vor constriction, permeability, leukocyte adhesion, thrombosis, and pr oliferation. Altered endothelial synthetic activities include an incre ased production of matrix proteins that may underlie intimal thickenin g at flow dividers and curvatures. In the presence of hyperlipoprotein emia, endothelial hyperpermeability, as determined by flow mechanics, and accumulation of subendothelial matrix proteins may favor intimal u ptake and retention of low-density lipoprotein (LDL). Local oxidative degradation of trapped LDL may generate lipid-derived inflammatory med iators, such as oxysterols, peroxidized fatty acids, and lysophospholi pids. Proinflammatory properties of the latter can explain some of the effects that are necessary for generating atherogenic mononuclear (mo nocytic/T-lymphocytic) inflammatory responses in arterial walls.