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Cellular events in atherosclerosis

Cellular events in atherosclerosis

Atherosclerosis is the greatest contributer to the progression of cardiovascular disease. The accumulation of 'fatty' substrates, such as lipids and cholesterol, and fibrous proteins hardens and narrows the arteries impairing blood flow. In arteries leading to organs this impaired blood flow can not only damage organ function but if the atherosclerotic plaque ruptures the resulting blood clot can completely block the supply of blood to an organ. If this occurs in the heart or the brain it can trigger life threatening events such as a heart attack or stroke. 

Arteries and veins typically have a triple layered structure (trilaminar). The thickness of these layers varies depending on the type of vessel and the layers are seperated by elastic fibres. In healthy arteries and veins the innermost layer of the blood vessel (intimal layer) consists of the monolayer of cells known as the endothelium and underlying supportive connective tissue. The endothelium is in direct contact with the blood and is important for maintaining the barrier between the blood and vessel wall. The medial layer is mainly comprised of vascular smooth muscle cells (VSMCs). The VSMCs, through contraction and relaxation, control blood pressure by altering the diameter of the blood vessel lumen. The medial layer is the thicker in arteries than veins as veins do not have to maintain blood pressure through VSMC contraction. 

Where does it all begin?

Unfortunately even as you read this you will most likely have fatty streaks in your large arteries. Not to worry, these fatty streaks do not result in any clinical complications. Fatty streaks are elevations of the intimal layer of the vessel wall and are composed of lipid-filled macrophages. They can form within the first decade of your life and although asymptomatic they can progress to atherosclerotic plaques. There are numerous risk factors which increase the progression of atherosclerosis; however, a high fat and high cholesterol diet is the most important factor.


The distribution of atherosclerotic legions is governed by hemodynamics (=blood flow movement). A change in blood flow, for example where a vessel bifurcates (=vessel branches), can cause laminar sheer stress and turbulence. Turbulent blood flow can trigger the initiation of atherosclerosis development. 


The different stages of atherosclerosis have been intensively investigated; however, the method of atherosclerosis initiation still remains unclear. There is no universal theory due to the complex aetiology. Evidence shows inflammation and immune mechanisms as critical regulatory processes of the disease. The main initiation hypothesis is the 'response to injury hypothesis' which was firstly described by Ross in 1972. An injurious agent, such as oxidised low-density lipoprotein, affects the endothelial surface and perturbs the intact monolayer. This initial injury could also be from a virus, toxin or a mechanical injury from turbulence. Thereafter, at the site of injury endothelial cells undergo many alterations including upregulating the expression of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) and E-selectin. This allows the adhesion and entry of monocytes and lymphocytes into the vessel wall. Endothelial damage also causes collagen to be exposed into the lumen which promotes adherence of monocytes and platelets to the endothelium. After injury, monocytes transmigrate across the damaged endothelium and enter the intimal layer of the vessel wall. These monocytes then differentiate into macrophages which ingest lipids. These lipid-laden macrophages are known as foam cells. These foam cells start the development of the fatty streak which can develop to a fibrous plaque. 

Atherosclerosis is driven by an inflammatory process in response to the initial injurious agent. Cytokines (protein mediators) play an important role in this inflammatory process. In the early stages of a fatty streak, cytokines can facilitate the migration of monocytes from the lumen into the vessel wall by disrupting endothelial progenitor cell junctions and inducing expression of adhesion molecules. Cytokines also stimulate the differentiation of macrophages into foam cells. Experiments in mice have shown that inhibition of certain cytokines can limit plaque development.


Cell death, through necrosis and apoptosis, is an important facilitator of plaque progression and stability. Apoptosis and necrosis in atherosclerotic plaques can be triggered by oxidised low-density lipoproteins (ox-LDL).

Necrosis within atherosclerotic plaques has not been as intensively investigated as apoptosis due to the low availability of in vivo methods of detection. Examination of plaques with the transmission electron microscopy shows that dying foam cells and VSMCs within the plaque undergo necrosis.  When cells within the plaque become necrotic they release their contents into the plaque. These cellular contents contribute to the formation of the necrotic core. This core region consists of lipids, such as cholesterol, and cell debris. Extracellular matrix proteins, such as collagen, are not present within the necrotic core.

Normally when cells undergo apoptosis they are cleared by macrophages. This process is impaired in atherosclerotic plaques which promotes inflammation and further contributes to the necrotic core.  The level of apoptosis is related to the progression stage of the plaque. Advanced fibrous plaques are seen to have higher levels of apoptosis. The level of apoptosis is believed to correlate with the accumulation of foam cells. 


Fibrous plaques can be considered stable; however, the release of matrix metalloproteinases (MMPs) by foam cells break down the extracellular matrix of the fibrous cap. This causes the fibrous cap to thin and decreases plaque stability. It has been suggested that MMPs could also contribute to the apoptosis of surrounding cells through the cleaving of apoptotic 'death' ligands which can trigger apoptosis through paracrine or autocrine mechanisms. As the soft necrotic lipid core increases in size and the fibrous cap thins the stability of the plaque decreases which will eventually lead to plaque rupture. The formation of a thrombus can lead to acute occlusion of a vessel which results in complete blockage of the blood flow to an organ. 


Further reading

For one of the original reviews by the ‘godfather’ of atherosclerosis; Ross:

  • Ross (1995) Cell biology of atherosclerosis. Annual reviews of physiology 57. Pages 791-804.

For a more in depth overview of atherosclerosis:

  • Lusis (2000) Atherosclerosis. Nature 407. Pages 233-241.

For more information on the role of macrophages in the progression of plaques:

  • Schrijvers et al., (2007) Phagocytosis in atherosclerosis; Molecular mechanisms and for plaque progression and stability. Cardiovascular Research 73. Pages 470-480.

For more information on the role of inflammation in atherosclerosis:

  • Libby et al., (2009) Inflammation in atherosclerosis. Journal of the American College of Cardiology 54. Pages 2129-2138.

For an excellent review of the vast number of cytokines involved in atherosclerosis:

  • Ait-Oufella et al., (2011) Recent advances on the role of cytokines in atherosclerosis. Arteriosclerosis Thrombosis and Vascular Biology 31. Pages 969-979.

For more information on the role of necrosis and apoptosis in atherosclerosis:

  • Kockx M.M., Herman A.G. (2000) Apoptosis in atherosclerosis; beneficial or detrimental? Cardiovascular research 45. Pages 736-746.  
  • Martinet W., Schrijvers D.M., De Mayer G.R.Y. (2011) Necrotic cell death in atherosclerosis. Basic Research in Cardiology 106. Pages 749-760.

For a good overview of the clinical problems of atherosclerosis:



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