ATHEROSCLEROSIS

The arterial wall is a dynamic and regulated system, but noxious elements can disturb normal homeostasis and pave the way for atherogenesis. Atherogenesis can be divided into five key steps, which are 1) endothelial dysfunction 2) formation of lipid layer or fatty streak within the intima 3) migration of leukocytes and smooth muscle cells into the vessel wall 4) foam cell formation 5) deposition of extracellular matrix Via these consecutive steps, an atherosclerotic plaque is formed. The formation of the plaque can also be divided into three major stages: 1) the fatty streak, which represents the initiation 2) plaque progression, which represents adaption 3) plaque disruption, which represents the clinical complication of atherosclerosis

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FATTY STREAK The earliest visible signs of atherogenesis are the fatty streak. Fatty streaks represent the earliest visible lesions of atherosclerosis. They appear as areas of yellow discoloration on the arterys inner surface. At this stage of initiation, the fatty streak doesnt protrude substantially into the artery wall nor impedes blood flow. This process is already visible in most people by the age of 20 They do not cause symptoms, and in some locations in the vasculature, they may regress over time The precise initiation of fatty streak development is still not known, but in the animal, various stressors cause early endothelial dysfunction. Endothelial dysfunction allows entry and modification of lipids within the subendothelial space, where they serve as proinflammatory mediators that initiate leukocyte recruitment and foam cell formation.

Endothelial Dysfunction Injury to the arterial endothelium represents a primary event in atherogenesis. It can be caused by physical or chemical stressor. There are two atheroprotective endothelial functions from physical stress : When endothelial cells are exposed to laminar flow, they secrete NO. NO functions as an anti-atherosclerotic substance through vasodilation, inhibition of platelet aggregation and antiinflammatory effects. The second function is executed, when exposed to laminar flow by an expression of the antioxidant enzyme superoxide dismutase.

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This enzyme performs anti-atherosclerotic role by acting against reactive oxygen species, which are produced by chemical irritants or transient ischemia in the vessel. These two atheroprotective endothelial functions can be impaired by several factor : First is physical factor. The disturbed flow (low shear stress with rapid fluctuations), which is typically located at arterial branch points and bifurcations, can impair the protective functions. arteries with few branches (e.g., the internal mammary artery) show relative resistance to atherosclerosis, whereas bifurcated vessels (e.g., the common carotid and left coronary arteries) are common sites for atheroma formation Second is chemical factor. Tobacco smoking, abnormal circulating lipid levels, and diabetes. Each of these states increases endothelial production of reactive oxygen speciesnotably, superoxide anionwhich interact with other intracellular molecules to influence the metabolic and synthetic functions of the endothelium.

Lipoprotein Entry and Modification Disruption of the integrity of endothelial barrier due to endothelial dysfunction allows the passage of circulating lipoproteins (low-density lipoprotein, LDL) into the intima. Once within the intima, LDL accumulates in the subendothelial space by binding to components of the extracellular matrix known as proteoglycans. This accumulation is a critical process in atherogenesis since LDL may undergo chemical modifications while residing longer in the intima. Chemical modification occurs with LDL when chronic accumulation takes place inside the intima. Oxidation is one type of chemical modification. It can result from the local action of reactive oxygen species and pro-oxidant enzymes derived from activated endothelial or smooth muscle cells, or from macrophages that penetrate the vessel wall. Furthermore, the oxidized LDL molecule induces tissue damage. It also induces leukocyte recruitment and foam cell formation in the fatty streak throughout the plaque development.

Leukocyte Recruitment Recruitment of leukocytes (primarily monocytes and T lymphocytes) to the vessel wall is a key step in atherogenesis. It is depend on two important factors : o Expression of leukocyte adhesion molecules (LAM), which are the immunoglobulin gene superfamily (particularly, vascular cell adhesion molecule [VCAM-1] and intercellular adhesion molecule 1 [ICAM-1] , on the endothelial wall o Chemoattractant signals (e.g., monocyte chemotactic protein 1 [MCP-1], IL-8, interferoninducible protein-10) that direct diapedesis (passage of cells through the intact endothelial layer) into the subintimal space These two factors mainly direct monocytes to the atherosclerotic lesion. T lymphocytes that play a central role in the immune system reside within plaques at all stages of atherogenesis, mainly producing cytokines. As mentioned earlier, modified LDL can maintain leukocyte recruitment by inducing LAM and chemokine expression. It can also stimulate endothelial and smooth muscle cells to produce proinflammatory cytokines

Foam Cell Formation When monocytes enter the intima, they differentiate into phagocytic macrophages. These phagocytic macrophages may become foam cells when they absorb lipoproteins

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They dont phagocyte LDL with a classic cell surface LDL -receptor, since it does not recognize modified LDL, but with a family of scavenger receptors that do bind and internalize modified LDL Uptake by scavenger receptors avoids negative feedback inhibition from the high cholesterol content unlike the classic LDL-receptors, and allows the macrophages to imbibe cholesterol-rich lipid that results into the formation of foam cells This uptake seems to be beneficial at first sight, since it absorbs the inflammatory modified-LDL, however since these foam cells have impaired trafficking, they will be locally accumulated in the plaque and encourage the plaque progression by serving as a source of proinflammatory cytokines.

PLAQUE PROGRESSION Whereas endothelial cells play a central role in formation of the fatty streak, smooth muscle cell migration into the intima dominates early plaque progression. The atherosclerotic plaque at this stage is called fibrous cap atheroma featuring two characteristics, which are lipid-rich necrotic core and encapsulation by a fibrous cap. The fibrous cap is an area between the vessel lumen and the core of the plaque, which contains dead foam cells, macrophages, smooth muscle cells, lymphocytes and extracellular matrix A distinctive hallmark of this phase is necrosis with macrophage infiltration around a lipid pool and loss of proteoglycans or collagen At this point, the deposition of free cholesterol is not easily visible and the plaque does not always cause luminal restriction of blood flow due to a compensatory outward remodeling of the plaque wall. This remodeling preserves the diameter of the vessel lumen and thus may evade detection by angiography Progressive vessel narrowing may result in tissue ischemia and can cause symptoms such as angina pectoris or intermittent claudication of extremities

Smooth Muscle Cell Migration The transition from fatty streak to fi brous atheromatous plaque involves the migration of smooth muscle cells from the arterial media into the intima, After migration, smooth muscle cells proliferate within the intima and secrete extracellular matrix macromolecules. Additionally, foam cells, activated platelets and endothelium stimulate substances that induce the migration and accumulation of smooth muscle cells. For example, foam cells release platelet derived growth factor (PDGF), cytokines and growth factors that directly contribute to the migration and proliferation process, and they also activate smooth muscle cells and leukocytes to reinforce inflammation in the atherosclerotic lesion Although plaque progression is traditionally known as a gradual and continuous process, recent evidence claims that this process can be strongly accentuated by bursts of smooth muscle replication. The observation of small ruptures within the plaque occurring without any clinical symptoms or signs supports this suggestion. These small ruptures expose tissue factor secreted by foam cells that stimulates coagulation and microthrombus formation in the lesion. Such microthrombi contain activated platelets that release additional factors such as PDGF and heparinase that can further stimulate local smooth muscle cell migration and proliferation Heparinase stimulates smooth muscle cell migration and proliferation by degrading heparan sulfate, which normally counteracts this process

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Extracellular matrix metabolism Metabolic processes in extracellular matrix play a central role in bridging the plaque progression to plaque rupture. This process is influenced by the balance of matrix deposition synthesis by smooth muscle cells and degradation by matrix metalloproteinases (MMP), a class of proteolytic enzymes. For example, PDGF and TGF- stimulate interstitial collagen production, while inflammatory cytokines such as IFN- inhibits collagen synthesis On the other hand, inflammatory cytokines weaken the fibrous cap by stimulating local foam cells to secrete MMP that degrades collagen and elastin of the fibrous cap, and predispose fibrous cap to rupture

Plaque Disruption Plaque Integrity The size of the lipid core has biomechanical implications for the stability of the plaque. With increasing size and protrusion into the arterial lumen, mechanical stress focuses on the plaque border abutting normal tissue . In addition to bearing increased stress, local accumulation of foam cells and T lymphocytes at this site accelerates degradation of extracellular matrix, making this region the most common site of plaque rupture. The net deposition and distribution of the fibrous cap is an important determinant of overall plaque integrity. Whereas lesions with thick fibrous caps may cause pronounced arterial narrowing, they have less propensity to rupture Conversely, plaques that have thinner caps (and often appear less obstructive by angiography) tend to be fragile, and more likely to rupture and incite thrombosis

Thrombogenic Potential When the fibrous cap is ruptured, the highly thrombogenic components of the necrotic core, including tissue factor, gets in direct contact with the circulating monocytes in the blood. It is believed that these circulating monocytes in the blood play a stronger role as a source of tissue factor than the necrotic core. Tissue factor stimulates platelet activation and thus can initiate and propagate thrombus. The thrombus formed at the rupture site is called white thrombus due to its grossly white appearance of rich platelet. At the proximal and distal ends near the site of white thrombosis there is another type of thrombus composed of layers of red blood cells and fibrin and is therefore called red thrombus Inflammatory stimuli in the plaque environment incite smooth muscle cells, endothelial cells, and foam cells to release tissue factor that initiates the extrinsic coagulation pathway Inflammatory stimuli also stimulate expression of antifibrinolytics such as plasminogen activator inhibitor-1 and consequently enhance thrombosis, The activated endothelial cells also contribute to thrombosis and coagulation by depositing fibrin at the vascular wall. Thus, the inflammatory and dysfunctional condition of the plaque environment decreases the counterbalancing of coagulation and fibrinolysis, increasing the probability of

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major clinical complications of atherosclerosis.

Complications of atherosclerosis

Risk Factor Atherosclerosis