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Flashcards in Vascular biology of athersclerosis Deck (14):

Endothelium dysfunction in athersclerosis

-Normally endothelium maintain vascular tone by releasing vasodilators (NO)
-If they begin to dysfunction they reduce the release of vasodilators, increase release of vasoconstrictors, increase cytokines/inflammatory molecules and pro-thombotic molecules
-Primary cause of endothelial dysfunction: diet (and lack of exercise)
-3 things contribute to atherosclerosis: endothelium dysfunction, inflammation, and thrombosis



-Released by endothelial cells and cause smooth muscle relaxation
-Lead to vasodilation



-Released from endothelial cells, has 2 effects
-Primary effect is in smooth muscle cells, it causes them to contract
-But in endothelial cells it causes the release of NO


Oxidant stress on plaque formation

-Oxygen free radicals oxidize LDL to oxyLDL
-OxyLDL then inhibits synthesis of NO and inhibits NO function by oxidizing it
-Overall there is an increased chance of vasoconstriction, and this is worsened by high glc and BP
-OxyLDL also recruits cholesterol into the endothelium and forms plaque



-HDL is atheroprotective: it is responsible for reverse transport of cholesterol, removing it from peripheral tissues and returning it to the liver
-HDL also delivers antioxidants that can prevent HDL oxidation


Endothelial cell activation

-Get activated due to damage or oxidant stress
-Lead to expression and release of cytokines/chemokines
-Initiates inflammatory process


Classifications of atherosclerotic lesions (!)

-Type 1: minor changes (thickening) of the intima
-Type 2: macrophages recruited and begin consuming LDL/cholesterol, become foam cells (fatty streak in intima, under IEL)
-Type 3: small pools of extracellular lipid (preatheroma)
-Type 4: core of extracellular lipid (atheroma)
-Type 5: fibrous cap forms and thickens (fibroatheroma)
-Type 6: fibrous cap ruptures at shoulder, blood contacts the plaque and thrombus forms


Intraplaque hemorrhage (ruptures)

-Potentially clinically silent (95%), but for each silent event the artery narrows
-Progressive narrowing can lead to ACS (acute coronary syndrome) or healing w/ lumen stenosis (chronic stable angina, CSA)
-Thicker plaques will have greater capillary formation in the vasa vasorum to supply the expanded aerial wall
-These thicker plaques are also more likely to rupture
-Important to note that thicker doesn't mean smaller lumen, since the wall of the arteries can expand so much


Vascular remodeling

-Metalloproteinases (MMPs) and collagenases are abundant, and degrade collagen in plaque
-This weakens the plaque and makes it less resistant to mechanical forces
-This helps remodel the plaque to prevent stenosis
-Positive remodeling: vessel wall grows to accommodate the plaque while maintaining lumen size
-Use ratio of IEL/EEL; IEL/EEL>1.05 is + remodeling, if the ratio is <.95 its negative remodeling


Negative and positive remodeling

-Positive remodeling plaques are less stable and more likely to rupture
-In this case, there is less stenosis (stenosis is <50% b/c lumen relatively intact)
-These plaques generally have thinner fibrous caps and thicker plaques
-Negative remodeled plaques are more stable and less likely to rupture
-They have a great deal of stenosis (usually 80-90%), thick fibrous walls, and thinner plaques
-Negative remodeling more likely to cause CSA, positive remodeling more likely to cause ACS


Dangers of positive remodeling

-These plaques have more macrophages, more lipid-rich atheroma, and more MMPs (unstable)
-They also have less collagen, less smooth muscle and thinner cap
-Therefore majority of MIs (ACS) are caused by positive remodeling plaques, when stenosis is <50%
-If the stenosis is 70-80% it means the plaque has already ruptured and healed several times, thus is now stable and unlikely to cause ACS


Markers of a vulnerable plaque

-Large lipid core w/ fat-induced inflammation
-Abundant MMPs (MMP 2, 3, and 9) therefore low collagen content
-Decreases matrix synthesis and increases matrix degradation
-Thin fibrous cap, possible mural platelet and fibrin
-Endothelial dysfunction/damage
-High SMC apoptosis


Risk factors contributing to plaque formation

-Diet most important (excess lipid)
-Lack of exercise
-HTN, diabetes


Rx of atherosclerosis

-Statins: decrease LDL
-Raise HDL: niacin, fish oil
-ACE inhibitors (HTN)
-Aspirin w/ clopidogrel (antiplatelets)
-Warfarin (antithrombotics)