Atherosclerosis Flashcards
What are the layers of the arterial wall?
Intima – single layer of endothelial cells
Media – consists of smooth muscle and extracellular matrix, and subserve the contractile and elastic function of the vessel. It is separated by elastin layers.
Adventitia – contain the nerve, lymphatic and blood vessels.
How does normal endothelial cells work as anti-thrombin molecules?
Normal endothelial cells process anti-thrombin molecules. Some reside on the endothelial surface (heparan sulfate, thrombomodulin and plasminogen activator), while other products enter the circulation (e.g., prostaglandin I2 and nitric oxide (NO)). Endothelial cells secret substance (such as vasodilator and vasoconstrictors) that modulate the underlying muscle layer to alter the resistance and the luminal blood flow.
What do vascular smooth muscle cells produce?
Collagen, elastic and proteoglycans which forms the vascular extracellular matrix. They also can synthesize vasoactive and inflammatory mediators (such as IL-6 and TNF-α).
What does the extracellular matrix of the artery made of? What is its function?
Fibrillar collagen, proteoglycan, and elastin make up most of the extracellular matrix, and they are responsible for the strength and flexibility of the arteries. The extracellular matrix regulated the growth of its resident cells.
What are the stages mechanism of atherosclerotic lesion?
Fatty streak
Plaque progression
Plaque disruption.
Explain the mechanism for fatty streaks production!
Endothelial dysfunction allows the entry and modification of lipids within the subendoteliala space. Lipids within the endothelial space serve as proinflammatory mediators that initiate leukocytes recruitment and foam cells formation.
Explain endothelial dysfunction role in atherosclerosis!
Injury (due to physical force or chemical irritants) to the arterial endothelium represents a primary event in atherogenesis. In straight sections of arteries, the normal laminar shear forces favor the endothelial production of NO. Laminar flow increase the expression of the antioxidant enzyme superoxide dismutase, which protects against reactive oxygen species produced by chemical irritants or transient ischemia. However, disturbed flow occurs at arterial branch point.
Endothelial dysfunction my result from tobacco smoking, abnormal circulating lipid level and diabetes. These risk factors increase the production of reactive oxygen species (superoxide anion) that interact with intracellular molecules. In such an environment, the cells promote local inflammation. This interrupt the endothelial role as a permeability barrier and alter the release of vasoactive substance and interfere with normal anti-thrombotic properties.
Explain the mechanism of lipoprotein entry to the intima and modification!
Increased endothelial permeability allows the entry of low density lipoprotein (LDL) into the intima, a process facilitated by an elevated circulating LDL concentration. On the other hand, several monogenic causes of elevated LDL exist, including mutations in the LDL receptor, apolipoprotein B, and PCSK9 (a protease involved in regulation of the LDL receptor). Once within the intima, the LDL pound to the proteoglycans. Hypertension may promote retention of lipoproteins in the intima by accentuating the production of LDL-binding proteoglycans by smooth muscle cells.
The reactive oxygen species and pro-oxidant enzyme derived from endothelial or smooth muscle cell or from macrophages oxides the LDL that are trapper in the subendothelial cells. The microenvironment of the subendothelial space can isolated oxidized LDL from anti-oxidants in the plasma. In diabetic patients with sustained hyperglycemia, glycation of the LDL can occur – a modification that can provide the LDL antigenic and pro-inflammatory.
How does hypertension promote retention of lipoproteins in intima?
intima by accentuating the production of LDL-binding proteoglycans by smooth muscle cells
Explain the mechanism for leukocytes recruitment!
Recruitment depends on the expression of LAM (ICAM-1 and selectin) on normally non-adherent endothelial cells, and on chemoattractant signals (e.g., monocytes chemotactic protein 1 (MCP-1), IL-8, interferon-inducible protein 10).
mLDL (modified LDL) can induce LAM, chemoattractant cytokine and stimulates endothelial and smooth muscle cells to produce pro-inflammatory cytokine.
Explain the mechanism for foam cell formation!
The macrophages engulf the mLDL with their scavenger receptors that bind and neutralize mLDL. mLDL ingested by scavenger receptor evades negative feedback inhibition and permits swelling of the macrophages with cholesterol and cholesteryl ester, resulting in foam cells. The accumulation of lipid, stress the macrophages and cause them to go apoptosis. The lipid-rich center of a plaque, formed by necrotic foam cells, is called necrotic core.
Explain plaque progression! Both the early plaque growth and late plaque growth!
The atherosclerotic plaque acquires a distinct thrombogenic lipid core that underlies a protective fibrous cap. Early plaque growth shows a compensatory outward remodeling of the arterial wall that preserves the diameter of the lumen and permits the plaque accumulation without the limitation of the blood flow. Later plaque growth can outstrip the compensatory arterial enlargement, restrict the vessel lumen, and impede perfusion.
Explain the mechanism for smooth muscle cell migration
The transition of the fatty streak to fibrous atheromatous plaque involves the migration of smooth muscle for media into the intima, proliferation of the smooth muscle within the intima, and secretion of extracellular matrix. The endothelial cells elaborate signal smooth muscle cell migration and proliferation. Foam cells produce factors that contribute to smooth muscle cell recruitment. For example, they release platelet-derived growth factor (PDGF) which stimulate the migration of smooth muscle cells across the internal elastic lamina and into the subintimal space, where they can replicate. PDGF stimulates the growth of residual smooth muscle cells in the intima. Foam cells also release cytokines and growth factors (TNF-α, IL-1, fibroblast growth factor, and TGF-β) that urge smooth muscle cell proliferation and synthesis of extracellular matrix proteins.
The plaque growth is punctuated by subclinical events with bursts of smooth muscle replication. Small breaches in the plaque integrity can expose tissue factor from foam cells, which activate coagulation and microthrombus formation. Activated within such microthrombi release potent factors (including PDGF and heparinase) that can spur a local wave of smooth muscle cell migration and proliferation. Heparinase degrades heparan sulfate (which normally inhibits smooth muscle cells migration and proliferation).
Explain how extracellular matrix metabolism is effected! What factors stimulate/inhibit collagen production?
Smooth muscle cells favor fortification of the fibrous cap. Net matrix deposition depends on the balance of synthesis by smooth muscle cells and degradation, mediated in part by a class of proteolytic enzymes know as matrix metalloproteinase (MMP). PDGF and TGF-β stimulate smooth muscle cell production of interstitial collagens. While INF-γ inhibit smooth muscle cell collagen synthesize. Inflammatory cytokines stimulate local foam cells to secrete collagen- and elastin degrading MMP, thereby weakening the fibrous cap and predisposing it to rupture.
What determine plaque integrity?
The size of the lipid core has the 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 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. Plaques that have thinner caps tend to be fragile, and more likely to rupture and incite thrombosis. Clinical terminology describes the spectrum of integrity as “Stable plaques” (marked by a thick fibrous cap and small lipid core) or “vulnerable plaques” (marked by a thin fibrous cap, rich lipid core, extensive macrophages infiltrate, and a little amount of smooth muscle).
