Nature 407(6801): 233-241

Atherosclerosis

Department of Medicine, Department of Microbiology, Immunology and Molecular Genetics, Department of Human Genetics, and Molecular Biology Institute, University of California, Los Angeles, California 90095, USA (ude.alcu.tendem@sisulj)

Abstract

Atherosclerosis, a disease of the large arteries, is the primary cause of heart disease and stroke. In westernized societies, it is the underlying cause of about 50% of all deaths. Epidemiological studies have revealed several important environmental and genetic risk factors associated with atherosclerosis. Progress in defining the cellular and molecular interactions involved, however, has been hindered by the disease’s aetiological complexity. Over the past decade, the availability of new investigative tools, including genetically modified mouse models of disease, has resulted in a clearer understanding of the molecular mechanisms that connect altered cholesterol metabolism and other risk factors to the development of atherosclerotic plaque. It is now clear that atherosclerosis is not simply an inevitable degenerative consequence of ageing, but rather a chronic inflammatory condition that can be converted into an acute clinical event by plaque rupture and thrombosis.

Abstract

Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The anatomy of a normal artery is shown in Fig. 1. The early lesions of atherosclerosis consist of subendothelial accumulations of cholesterol-engorged macrophages, called ‘foam cells’. In humans, such ‘fatty streak’ lesions can usually be found in the aorta in the first decade of life, the coronary arteries in the second decade, and the cerebral arteries in the third or fourth decades. Because of differences in blood flow dynamics, there are preferred sites of lesion formation within the arteries. Fatty streaks are not clinically significant, but they are the precursors of more advanced lesions characterized by the accumulation of lipid-rich necrotic debris and smooth muscle cells (SMCs). Such ‘fibrous lesions’ typically have a ‘fibrous cap’ consisting of SMCs and extracellular matrix that encloses a lipid-rich ‘necrotic core’. Plaques can become increasingly complex, with calcification, ulceration at the luminal surface, and haemorrhage from small vessels that grow into the lesion from the media of the blood vessel wall. Although advanced lesions can grow sufficiently large to block blood flow, the most important clinical complication is an acute occlusion due to the formation of a thrombus or blood clot, resulting in myocardial infarction or stroke. Usually, the thrombosis is associated with rupture or erosion of the lesion.

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Figure 1

Structure of a normal large artery. A large artery consists of three morphologically distinct layers. The intima, the innermost layer, is bounded by a monolayer of endothelial cells on the luminal side and a sheet of elastic fibres, the internal elastic lamina, on the peripheral side. The normal intima is a very thin region (size exaggerated in this figure) and consists of extracellular connective tissue matrix, primarily proteoglycans and collagen. The media, the middle layer, consists of SMCs. The adventitia, the outer layer, consists of connective tissues with interspersed fibroblasts and SMCs.

The events of atherosclerosis have been greatly clarified by studies in animal models, including rabbits, pigs, non-human primates and rodents. Mice deficient in apolipoprotein E (apoE) or the low-density lipoprotein (LDL) receptor develop advanced lesions and are the models most used in genetic and physiological studies¹. Figure 2 shows stages in the development of atherosclerotic plaques in experimental animals. The first observable change in the artery wall following the feeding of a high-fat, high-cholesterol diet is the accumulation of lipoprotein particles and their aggregates in the intima at sites of lesion predilection (Fig. 2a, b). Within days or weeks, monocytes can be observed adhering to the surface of the endothelium. The monocytes then transmigrate across the endothelial monolayer into the intima, where they proliferate, differentiate into macrophages and take up the lipoproteins, forming foam cells (Fig. 2c, d)². With time, the foam cells die, contributing their lipid-filled contents to the necrotic core of the lesion. Some fatty streaks subsequently accumulate SMCs, which migrate from the medial layer. With the secretion of fibrous elements by the smooth muscle cells, occlusive fibrous plaques develop and increase in size. Initially, the lesions grow towards the adventitia until a critical point is reached, after which they begin to expand outwards and encroach on the lumen. The lesions continue to grow by the migration of new mononuclear cells from the blood, which enter at the shoulder of the vessel; this is accompanied by cell proliferation, extracellular matrix production and the accumulation of extracellular lipid (Fig. 2e). Atherogenesis can be viewed as a ‘response to injury’, with lipoproteins or other risk factors as the injurious agents²3.

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Figure 2

Stages in the development of atherosclerotic plaques. a, In the first stages, lipoprotein is trapped in the subendothelial matrix. The freeze-etch electron micrograph shows the accumulation of 23-nm LDL particles (circled) in the matrix of a rabbit atrial-ventricular valve following incubation with LDL (inset). An endothelial cell at lower left shows the plasma membrane (MEMB) and cytoplasma (CYTO)⁷¹. Magnification ×141,372; scale bar, 0.1 μm. b, Lipoprotein aggregation is seen in this freeze-etch electron micrograph of rabbit intima following administration of a bolus of LDL. The aggregated particles are surrounded by matrix and collagen fibrils (asterisk)⁷². Magnification ×52,876; scale bar, 0.2 μm. c, Monocyte transmigration. The thin-section electron micrograph of a cross-section of the aorta of a 9-week-old apoE-deficient mouse shows a monocyte (arrow) moving between two endothelial cells (arrowheads) to enter the intima (int). The asterisk denotes a cluster of lipid underneath the endothelial cell¹. Magnification ×10,078; scale bar, 0.5 μm. d, Foam-cell formation. Freeze-etch electron micrograph of the cytoplasm of a macrophage foam cell in the intima of a rabbit fed a high-fat diet for two weeks. Large lipid droplets with the onion skin configuration typical of cholesterol esters (ce) as well as other lipid-filled compartments (arrows) can be recognized. Some compartments contain large aggregated LDL particles (asterisk) resembling those in b. Magnification ×21,542; scale bar, 0.5 μm. e, Fibrous lesion. Light micrograph (×400) of a section of an advanced human coronary atherosclerotic lesion that has been immunostained for the macrophage-specific antigen EMB-11 (red). A, adventitia; I, intima; IEL, internal elastic lamina; M, media. Photographs courtesy of A. Mottino, J. Frank and T. Drake, UCLA.

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