Proatherosclerotic events: pathobiochemical changes occurring in the arterial wall before monocyte migration.

The inception of experimentally induced atherogenesis is marked by subtle biochemical and ultrastructural changes of the arterial intima, modifications that precede the monocytes migration within the vessel wall. Long before any recognizable endothelial denudation, hypercholesterolemia induces a sequence of prelesional events that start with the enhanced transport of excess plasma lipoproteins especially by transcytosis, followed by intima accumulation of chemically (oxidatively) modified and reassembled lipoproteins (MRLp). Exposure of endothelial cells concomitantly to hypercholesterolemia on the luminal side, and to the MRLp cytotoxic effects on the abluminal side, generates endothelial dysfunctions with altered biosynthetic activities. The latter are manifested initially by the hyperplasia of basal lamina and its disjunction from endothelium, and by the proliferation and reorganization of a modified extracellular matrix that traps MRLp. The cytotoxic effects of MRLp contribute to the endothelial production of chemoattractants and adhesion molecules that are instrumental in monocyte recruitment and migration in the subendothelium, where activated and differentiated as macrophages, they avidly ingest MRLp and their complexes to form foam cells. The latter are the hallmark of fatty streaks that marks the transition from the prelesional to the lesional stage of atherogenesis. Understanding the earliest biochemical alterations of the artery wall is a prerequisite for designing more successful means of prevention and treatment of atherosclerosis.