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Atherosclerosis: Difference between revisions
→Leukocyte recruitment
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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 such as IL-1 and TNF-α. These proinflammatory cytokines can also induce LAM and chemoattractant cytokine expression equivalent to modified LDL. Therfore, the dual ability of modified LDL can directly or indirectly promote leukocyte recruitment and throughout atherogenesis. | 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 such as IL-1 and TNF-α. These proinflammatory cytokines can also induce LAM and chemoattractant cytokine expression equivalent to modified LDL. Therfore, the dual ability of modified LDL can directly or indirectly promote leukocyte recruitment and throughout atherogenesis. | ||
===Foam cell formation=== | |||
When monocytes enter the intima, they differentiate into phagocytic macrophages. These phagocytic macrophages may become foam cells when they absorb lipoproteins. They don’t uptake LDL from a classic cell surface LDL-receptor, since it does not recognize modified LDL, but from 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 when these foam cells have impaired outflow, they will be locally accumulated in the plaque and encourage the plaque progression by serving as a source of proinflammatory cytokines. | |||
===Plaque progression=== | |||
Smooth muscle cells are the ones who play a central role in plaque progression. Atherosclerotic plaque has two typical features, which are thrombogenic lipid core and a protective fibrous cap. Plaque growth does not always cause luminal restriction of blood flow at an early stage thanks to a compensatory outward remodeling of the plaque wall. This remodeling preserves the diameter of the vessel lumen and thus may even evade detection by angiography. Nevertheless, plaque growth at a later stage may result in ischemia due to the narrowing of the vessel and can cause ischemic symptoms such as angina pectoris or intermittent claudication. | |||
===Smooth muscle cell migration=== | |||
Migration of smooth muscle cell from the media to the intima is a distinctive indication of transition from fatty streak to plaque formation. After the migration, smooth muscle cells proliferate within the intima and secrete extracellular matrix macromolecules. | |||
Additionally, foam cells, activated platelets, and endothelium stimulate the substances that signal the migration and proliferation of smooth muscle cell. 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 cell and leukocyte to reinforce inflammation in the atherosclerotic lesion. | |||
Although plaque progression is traditionally known as a gradual and continuous process, recent evidence claim 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 microthrombus contains activated platelets that release additional factors such as PDGF and heparinase that can further stimulate local smooth muscle cell migration and proliferation. Heparinase stimulate smooth muscle cell migration and proliferation by degrading heparin sulfate, which normally counteracts this process. | |||
===Extracellular matrix metabolism=== | |||
Metabolic process in extracellular matrix plays a central role in bridging the plaque progression to plaque rupture. Ultimately, this process weakens the fibrous cap, predisposing it to 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-β stimulate interstitial collagen production, while inflammatory cytokines such as IFN-γ inhibits collagen synthesis. Inflammatory cytokines also weakens the fibrous cap by stimulating local foam cells to secrete MMP that degrades collagen and elastin of the fibrous cap. | |||