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Biology and pathology of atherosclerosis 

Biology and pathology of atherosclerosis

Chapter:
Biology and pathology of atherosclerosis
Author(s):

Robin P. Choudhury

and Edward A. Fisher

DOI:
10.1093/med/9780199204854.003.161301_update_001

Update:

This chapter has been completely revised, and now includes content from retired Chapter 16.13.3.

Updated on 29 Oct 2015. The previous version of this content can be found here.
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date: 30 March 2017

Formation of an atheromatous plaque—this is an inflammatory process that involves the contribution of endothelial cells, monocytes, and smooth muscle cells in conjunction with the deposition of atherogenic lipoproteins in the intimal layer of the vascular wall. The initial stage involves activation of the endothelium at regions of nonlaminar flow in vessels resulting in increased permeability to Apo B-containing lipoproteins (LDL). Inflammatory cells, in particular monocytes, are recruited into the intimal layer of the vessel wall via the action of chemokines and adhesion molecules mobilized by activated endothelium.

Progression of atheroma—ingestion of LDL by monocytes, predominantly via scavenger receptors, generates lipid-rich foam cells. Atheroma progression is promoted by the failure to clear macrophages and foam cells that, on dying, release cholesterol-rich material promoting further inflammation. Leucocytes and endothelial cells also contribute through the release of growth factors that stimulate proliferation of vascular smooth muscle cells (VSMC). These cells migrate from the medial layer to the intima where they undergo transformation to both a synthetic phenotype (contributing to extracellular matrix formation), and ‘macrophage-like’ vascular smooth muscle cells capable of phagocytosis of LDL.

Further development of the atheromatous plaque—extracellular matrix formation by VSMC is stimulated by cytokines (e.g. TGFβ‎ and platelet-derived growth factor) released from T cells, platelets, and macrophages. The extracellular matrix confers structural integrity to the atheromatous plaque and the overlying collagen-rich fibrous cap and promotes retention of lipoprotein molecules. Neovascularization of atheroma via the action of vascular endothelial growth factor (VGEF) results in susceptibility to plaque haemorrhage. Calcification is common although its pathogenic significance is uncertain. The progression of the atheromatous plaque is not always linear.

Clinical manifestations—stable angina may arise from progressive narrowing of the vessel lumen, but may also be contributed to by minor plaque rupture or haemorrhage resulting in stepwise progression. Acute coronary syndromes arise from more serious abrupt transformations of atheromatous plaques due to plaque haemorrhage, erosion, and rupture. Atheromatous lesions with a large lipid-rich core and thin fibrous cap are predisposed to plaque rupture, releasing lipid-containing prothrombotic material and giving rise to thrombosis and acute occlusion. Thrombotic occlusion due to plaque erosion arises in areas denuded of endothelium and is more common in women smokers.

Medical management—therapies to promote atheroma regression target plasma lipid profiles, plaque inflammation, and plaque remodelling. Dietary and pharmacological modification of plasma lipids are effective secondary prevention measures which have been shown to promote plaque regression, but their impact on clinical events appears to relate to complex mechanisms which modify inflammation, plaque stability, and thrombosis and are more difficult to assess using current techniques. Specific therapies targeting the inflammatory component of the atheromatous plaque, in particular monocyte recruitment, macrophage function, and apoptosis, are theoretically attractive and are currently under development.

Initiation of atheroma

Atherosclerotic plaques are not randomly distributed, but tend to form at the inner curvatures and branch points of arteries, where laminar flow is either disturbed or insufficient to support the normal, quiescent state of the endothelium (the lining of endothelial cells that separates the circulating blood from the arterial wall). The resulting activation of the endothelium leads to increased permeability to lipoproteins and an accumulation of extracellular matrix proteins that cause diffuse intimal thickening and the retention of the atherogenic apolipoprotein B (apoB)-containing lipoproteins.

Endothelial activation also promotes the recruitment of circulating monocytes that originate from either the bone marrow or spleen. Monocyte entry into the arterial intima depends on endothelial cell up-regulation of molecules that mediate their arrest on the luminal surface of the endothelium. The recruited monocytes transmigrate across the endothelium, where they differentiate into macrophages, some of which encounter the retained apoB-lipoproteins. The subsequent uptake of the retained apoB-lipoproteins by these macrophages is one of the earliest pathogenic events in the nascent plaque and results in the development of macrophage foam cells. The mechanisms of foam cell formation have been intensely studied. Although macrophages can take up apoB-containing lipoproteins through the low-density lipoprotein (LDL) receptor, expression of this receptor is down-regulated early during foam cell formation by the increased cellular cholesterol levels. These observations led to the hypothesis that lipoproteins must become modified in the artery wall and be taken up by other mechanisms, notably by scavenger receptors. Multiple means of LDL modification that facilitate cholesterol loading of macrophages in vitro have been identified, including oxidation. The physiologically relevant in vivo pathways of foam cell formation are still debated, though it is widely accepted that the appearance of foam cells in arterial sites represents the initiation of an atherosclerotic plaque.

Leucocyte recruitment

Though many cell types contribute to the formation of atherosclerotic plaques, including endothelial cells, monocytes, dendritic cells (DCs), lymphocytes, eosinophils, mast cells, and smooth muscle cells, macrophage foam cells are so central in the initiation and progression of atherosclerosis that emphasis has long been placed on understanding the mechanisms of monocyte recruitment into plaques. Circulating monocytes in mice consist of two major subsets, LY6Chi and LY6Clow, with the corresponding subsets in humans being CD14+CD16- and CD14lowCD16+. In mice, and presumably in humans, the more inflammatory monocyte subsets (LY6Chi and CD14+CD16-) make up the majority of cells recruited to progressing atherosclerotic plaques and are thought to be the source of the M1 (classically activated) macrophages found in both murine and human plaques that are responsible for maintaining a chronic inflammatory state.

Monocyte recruitment, as noted above, begins at the luminal surface of the endothelium. The capture and rolling phases of the recruitment cascade depend on the immobilization of chemokines, particularly CC-chemokine ligand 5 (CCL5) and CXC-chemokine ligand 1 (CXCL1), to endothelial cell glycosaminoglycans, and on P-selectin, which is expressed on the luminal side of endothelial cells. Vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), which bind to the integrins VLA4 and lymphocyte function-associated antigen 1 (LFA1), respectively, are important for the firm adhesion of monocytes to the luminal surface of the endothelium.

The next phase is the transmigration of monocytes across the endothelium into the intimal (subendothelial) space. This is mediated by chemokines secreted by endothelial cells, intimal macrophages, and smooth muscle cells. Although several chemokines have been implicated in atherosclerosis, the three major chemokine receptor-chemokine pairs involved in monocyte transmigration are CCR2-CCL2, CX3CR1-CX3CRL1, and CCR5-CCL5. In addition to these chemokines, CD31 (also known von Willebrand factor; an endothelial cell surface immunoglobulin-like adhesion molecule) and VCAM1 may also have a role in monocyte transmigration into atherosclerotic plaques.

Although most studies of monocyte recruitment have been conducted in mice, the key players described above all have human homologues thought to function in similar ways.

Progression of atheroma

Beyond plaque initiation (see ‘Initiation of atheroma’ earlier), two factors conspire to promote the progression of atheroma. These are the ongoing entry and subsequent retention of the apoB-containing lipoproteins, and the continued recruitment of monoctyes, which follow the same path as their predecessors, namely to become macrophages, then foam cells that exhibit inflammatory changes. The recruitment of these monocytes accelerates after plaque initiation because of increased expression on the endothelial surface of adhesion molecules (e.g. VCAM1 and ICAM1) and the robust secretion of attractant chemokines, particularly CCL-2 (also termed MCP-1), by multiple cell types in the plaque, including the already established macrophages and foam cells.

Recruitment of monocytes to a site of inflammation is not abnormal; rather, it is the failure to remove macrophages and resolve the inflammation that leads to pathology. In part this is due to macrophage chemostasis (cellular paralysis) that is not typical in other settings (such as in pneumonia or wound healing) and which might reflect the expression of retention molecules that render the macrophages and foam cells relatively unresponsive to chemokines, as shown in mice. There is at least one other contributing factor: as in other tissues, a fraction of the macrophage population in plaques undergoes apoptosis, and is normally phagocytosed by healthy macrophages in a process called ‘efferocytosis’. Even in an early plaque, in which the local environment is not fully toxic, clearance by efferocytosis cannot keep up with the influx of newly recruited monocytes, leading to plaque growth. As the disease advances, the plaque accumulates more inflammatory and injurious factors that can signal macrophages and other immune cells through Toll-like receptors (TLRs). Among other adverse effects, this reduces macrophage capacity to perform efferocytosis. This results in the disintegration of the dying macrophages, with the release into the extracellular plaque environment of inflammatory material, thrombotic factors, and the cholesterol-rich gruel found in the necrotic core.

In parallel with the macrophage ‘itinerary’ described above, as the atheroma advances, other immune cells—both innate (dendritic cells) and acquired (T and B lymphocytes)—also enter the plaque and modulate its inflammatory state. For example, T lymphocytes, depending on their stimuli, can either exacerbate macrophage activation by the secretion of Th1 cytokines (e.g. IL-1, IL-6, TNFα‎) or ameliorate it by secreting Th2 cytokines (e.g. IL-4, IL-10). Furthermore, B cells can elaborate antibodies to substances generated from the oxidation of LDL that resemble antigens derived from microorganisms, in an attempt to neutralize the harmful effects of these products, with levels of such antibodies considered by some as a marker of disease burden.

Smooth muscle cells

In normal arteries, vascular smooth muscle cells (VSMC) are confined to the medial layer, which is delimited from the intimal space, where plaques form and grow, and from the outer arterial wall by internal and external elastic laminae, respectively. The cells are in the ‘contractile’ state, meaning that they serve mainly to set the vascular tone in response to a variety of stimuli by either contracting or relaxing. Activated endothelial cells in coronary arteries not only up-regulate their leukocyte recruitment factors, they also down-regulate their production of nitric oxide, increasing arterial tone and adversely affecting blood flow to the myocardium. The loss of vasorelaxation is not the only change in VSMC in the progressing plaque. Both activated leucocytes and endothelium secrete growth factors that stimulate the proliferation of VSMC, which then migrate out of the medial layer into the intima. The migration of synthetic VSMC to the subendothelium and their elaboration of collagen forms the fibrous cap.

The historical view has been that the VSMC phenotype switches from ‘contractile’ to ‘synthetic’, in recognition of increased production of extracellular matrix (ECM) by these cells (see ‘Extracellular matrix’). However, it is now appreciated that the phenotypic spectrum of VSMC in atheroma is more complex than originally realized. For example, VSMC can gain properties of inflammatory cells presumably because their TLRs become stimulated as they do in macrophages (see previous section). Another way in which the VSMC phenotype can be altered is by accumulating lipids. Relative to macrophages, whose transition to foam cells is enabled by their expression of scavenger receptors that take up large amounts of lipoprotein-derived lipids well after their LDL receptors are down-regulated, VSMC appear to become engorged more through a phagocytic process. Once it occurs to a significant degree, however, the cells in vitro and in vivo assume a macrophage foam cell-like state, both morphologically and phenotypically (in terms of cell-specific marker expression). In advanced plaques in patients, it has been estimated that as much as 40% of cells that would be traditionally classified as macrophage foam cells are actually of VSMC origin. Unlike the subendothelial VSMC that retain the synthetic phenotype, it is likely that the ‘macrophage-like’ VSMC have negative effects on plaque inflammation and stability.

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