Formation of Atherosclerosis - Atherogenesis

Extracellular Lipid Accumulation

The first steps in atherogenesis in humans remain largely conjectural. However, integration of observations of tissues obtained from young humans with the results of experimental studies of atherogenesis in animals provides hints in this regard. On initiation of an atherogenic diet, one typically rich in cholesterol and saturated fat, small lipoprotein particles accumulate in the intima.
These lipoprotein particles appear to decorate the proteoglycan of the arterial intima, and tend to coalesce into aggregates. Detailed kinetic studies of labeled lipoprotein particles indicate that a prolonged residence time characterizes sites of early lesion formation in rabbits. The binding of lipoproteins to proteoglycan in the intima captures and retains these particles, accounting for their prolonged residence time. Lipoprotein particles bound to proteoglycan have increased susceptibility to oxidative or other chemical modifications, considered by many investigators to be an important component of the pathogenesis of early atherosclerosis.
Other studies suggest that permeability of the endothelial monolayer increases at sites of lesion predilection to LDL. Contributors to oxidative stress in the nascent atheroma could include NADH/NADPH oxidases expressed by vascular cells, lipoxygenases expressed by infiltrating leukocytes, or the enzyme myeloperoxidase.

Leukocyte Recruitment

Another hallmark of atherogenesis, leukocyte recruitment and accumulation, also occurs early in lesion generation. The normal endothelial cell generally resists adhesive interactions with leukocytes. Even in inflamed tissues, most recruitment and trafficking of leukocytes occurs in postcapillary venules, not in arteries. However, very early after initiation of hypercholesterolemia, leukocytes adhere to the endothelium and diapedese between endothelial cell junctions to enter the intima, where they begin to accumulate lipids and become foam cells.

The Focality of Lesion Formation

The spatial heterogeneity of atherosclerosis has proved challenging to explain in mechanistic terms. Equal concentrations of blood-borne risk factors such as lipoproteins bathe the endothelium throughout the vasculature. It is difficult to envisage how injury caused by inhaling cigarette smoke could produce any local rather than global effect on arteries. Yet, atheromas typically form focally, as revealed by studies of morphology, lipid accumulation, and adhesion molecule expression. Some investigators have invoked a multicentric origin hypothesis of atherogenesis, positing that atheromas arise as benign leiomyomata of the artery wall. The monotypia of various molecular markers such as glucose-6-phosphate dehydrogenase isoforms in individual atheroma supports this “monoclonal hypothesis” of atherogenesis. However, the location of sites of lesion predilection at proximal portions of arteries after branch points or bifurcations at flow dividers suggests a hydrodynamic basis for early lesion development. Arteries without many branches (e.g., the internal mammary or radial arteries) tend not to develop atherosclerosis.

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