Atherosclerosis Research

Pathogenesis of Atherosclerosis

Atherosclerotic plaques also contain cellular debris and, in advanced plaques, calcium deposits (in the form of hydroxyapatite) are often present. The plaque contents are highly thrombogenic and so are separated from the circulating blood by a fibrous cap, composed mainly of vascular smooth muscle cells and extracellular matrix proteins such as collagen, which are synthesized by these cells.

The exact cause of atherosclerosis remains unknown, but the initial process - termed 'atherogenesis' - involves the transmigration of monocytes/macrophages across the endothelium into the intima, where they scavenge oxidized lipid (ox-LDL), forming lipid-laden 'foam cells'. Expression of adhesion molecules by endothelial cells promotes this transmigration. Foam cells undergo apoptosis, forming a lipid-rich core within the developing plaque. The formation of a plaque within the arterial wall triggers an inflammatory response, propagated by the secretion of growth factors and chemokines by resident plaque cells.

Circulating macrophages, recruited to the atherosclerotic plaque through chemotaxis, are a major source of matrix metalloproteinases (MMPs) - zinc-dependent enzymes that degrade the fibrous cap, predisposing the plaque to rupture. MMPs may also degrade the elastic laminae between layers of the arterial wall, facilitating the migration of smooth muscle cells from the tunica media to the fibrous cap, thus helping strengthen it.

A thick smooth muscle-cell rich fibrous cap with a small lipid core is characteristic of a 'stable' plaque, that is, one which is less likely to rupture. Plaques with a thin fibrous cap and a large, necrotic lipid core are termed 'unstable' or 'vulnerable' plaques and are more susceptible to rupture. Any defect in the fibrous cap exposes the thrombogenic plaque contents to the circulating blood, triggering thrombosis. Ninety percent of these plaque ruptures are clinically silent, yet the remaining proportion trigger myocardial infarction or stroke, and can be fatal.

In addition to the recruitment of macrophages within an atherosclerotic plaque, other immune mediators are also present during atherosclerosis. The expression of a number of pro-atherogenic cytokines, including interleukin (IL)-1 and IL-6, are known to be upregulated in atherosclerotic plaques, and therefore targeting the receptors of these cytokines may hinder the progression of atherosclerosis. Whilst activation of the immune response within an atherosclerotic plaque may be detrimental, driving the progression and eventual rupture of a plaque, it may equally be beneficial in resolving the inflammation and clearing necrotic foam cells from the core of the plaque. Therefore, targeting the immune response in atherosclerosis may be a 'double-edged sword'.

Treatment of Atherosclerosis

Current therapeutics in atherosclerosis predominantly aim to reduce blood cholesterol, thereby limiting the expansion of an atherosclerotic plaque. Aside from lipid-lowering, a further potential avenue in the treatment of atherosclerosis is the coagulation cascade since it is the formation of an occlusive thrombus, not plaque rupture per se, which triggers the pathologies associated with atherosclerosis. Potential targets within the coagulation cascade include thrombin, urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA). Other mediators involved in platelet activation are also potential therapeutic targets in the prevention and treatment of atherothrombosis.