Inflammatory mechanisms of atheroma formation. Influence of fluid mechanics and lipid-derived inflammatory mediators.

Abstract

It has been suggested that atheroma formation is a chronic inflammatory response to lipid-derived inflammatory mediators accumulating at selected arterial sites. At large artery flow dividers and curvatures, secondary flow phenomena create zones of stagnation and recirculation that deprive endothelial cells of shear stress-induced differentiation. Endothelial cell phenotypes at these sites appear to represent activated cells expressing membrane-associated and secreted molecules that favor constriction, permeability, leukocyte adhesion, thrombosis, and proliferation. Altered endothelial synthetic activities include an increased production of matrix proteins that may underlie intimal thickening at flow dividers and curvatures. In the presence of hyperlipoproteinemia, endothelial hyperpermeability, as determined by flow mechanics, and accumulation of subendothelial matrix proteins may favor intimal uptake and retention of low-density lipoprotein (LDL). Local oxidative degradation of trapped LDL may generate lipid-derived inflammatory mediators, such as oxysterols, peroxidized fatty acids, and lysophospholipids. Proinflammatory properties of the latter can explain some of the effects that are necessary for generating atherogenic mononuclear (monocytic/T-lymphocytic) inflammatory responses in arterial walls.