L7 - Athersclerosis pathophysiology Flashcards
What is contained in the media of a BV?
SMC and ECM
What is contained in the adventitia of a BV?
nerves, lymphatics, BV
- nourishes cells of arterial wall
Describe role of normal endothelium?
- Produces anti-thrombotic molecules, preventing clotting
- Produces NO & prostacyclin which enter circulation
- Secretes substances that modulate SMC contraction
- Endothelial cells can modulate immune response
Compare and contrast a normal and an activated endothelial cell?
Normal
- impermeable to large molecules
- anti-inflammatory
- resist leukocyte adhesion
- resist thrombosis
Activated
- increased permeability
- increased inflammatory cytokines
- increased leukocyte adhesion molecules
- decreased vasodilators
- decreased anti-thrombotics
Compare and contrast a normal smooth muscle cell with an activated smooth muscle cell?
Normal
- normal contractile function
- maintains ECM
- contained in medial layer
Activated
- increased inflammatory cytokines
- increased ECM
- increased migration and proliferation into subintima
Describe how smooth muscle cells may promote leukocyte proliferation
- secrete IL-6, TNF-a
- promote leukocyte proliferation
- inducing endothelial expression of leukocyte adhesion molecules
Describe the ECM in healthy arteries?
- fibrillar collagen, proteoglycan, elastin
- native fibrillar collagen can inhibit SMC proliferation in vito
In an atherosclerotic wall, vascular endothelial and smooth muscle cells will react to?
inflammatory mediators such as IL-1 & TNF-a
Summarise the atherosclerotic inflammatory process?
- endothelial dysfunction
- accumulation of lipids in intima
- recruitment of leukocytes and SMC to vessel wall
- formation of foam cells
Evolution of the atheroslclerotic plaque
long answer, sorry!
- Lipoprotein accumulation intima
- Lipoprotein modification - darker aar of oxidation
- Oxidative stress and constituents of mLDL will induce local cytokine elaboration
- Increased expression of adhesion molecules which bind leukocytes. Increased expression of chemoattractants, monocyte chemoattractant protein 1 (MCP-1) which directs leukocyte migration into intima.
- After entering intima: blood monocytes encoutner stimulti such as macrophage colony stimulating factor (M-CSF) which augments their expression of scavenger receptors
- Scavenger receptor: increase lipoprotein uptake, promote development of foam cells
- Macrophage foam cell: addition cytokine source
- SMC migrate into intima from media
- Intimal SMC, divide, elaborate ECM - promotes matrix accumulation in growing athersclerotic plaque
- Increase intimal thickness, fatty streak develops and evolves into a fibro fatty lesion
- Calcification, fibrosis, SMC death
Role of scavenger receptors
How do they differ to classic LDL receptors
- mediate uptake of modified lipoprotein particles
- promote development of foam cells
- classic LDL receptors do not recognise chemically altered mLDL,
- hence macrophages rely on scavenger receptors that preferentially bind and internalise mLDL.
What response to endothelial cells have in response to injury?
secrete chemokines
- will attract WBC to area
Summarise stages of plaque development
- Fatty streak
- Plaque progression
- Plaque disruption
Formation of fatty streak
- endothelial dysfunction
- lipoprotein entry and modification
- leukocyte recruitment
- foam cell formation
Plaque progression
- SMC migration into intima
- will divide and elaborate ECM
- altered matrix synthesis and degradation
Plaque disruption
- disrupted plaque integrity
- haemodynamic stresses and degradation of ECM
- increase susceptibility of fibrous cap to rupture
- allowing superimposed thrombus formation
Fatty streak presents as..
Areas of yellow discoloration on the arteries inner surface
Endothelial dysfunction is the primary event in plaque in plaque initiation - how does this occur?
- Physical and chemical stresses alter the normal endothelium
- Will allow lipids entry into the subintima and promote inflammatory cytokine release
- Cytokine + lipid rich environment promotes recruitment of leukocytes to the subintima
- Once in subintima, leukocytes will become foam cells
- foam cells are a prominent inflammatory participant
Describe endothelial dysfunction as a result of exposure to a toxic chemical environment?
e.g. smoking, diabetes, circulating lipids
- increase endothelial production of reactive oxygen species, superoxide anion (v.constrictor)
- cells promote local inflammation
- activated endothelium: permeable, no longer barrier to lipids
Disadvantage of an activated epithelium
- increased endothelial permeability
- allows entry of LDL into intima
- LDL accumulates in subendothelial space by binding to a component of ECM known as proteoglycans
- LDL trapped within vessel wall for longer
- hence lipoprotein will undergo chemical modification
- contributing to development of athersclerotic lesion
Apoprotein
- directing lipoprotein to specific tissue receptors and mediating enzymatic reactions
Foam cell formation
- monocytes adhere, penetrate intima
- m.cyte –differentiates–> phagocytic m.phage
- m.phage imbibe proteins to form foam cells
M-LDL
modified low density lipoprotein
Describe a plaque that has been developing for many years
- typical athersclerotic plaque acquires a distinct thrombogenic lipid core that underlies a protective fibrotic cap
Describe early plaque growth effects on arterial wall
- compensatory outward remodelling of the arterial wall
- preserves the diameter of lumen
- permits plaque accumulation
How might tissue ischaemic arise from plaque growth?
- later plaque growth can outstrip the compensatory arterial enlargement, restricting vessel lumen
Symptoms of tissue ischaemia
- angina pectoris
- intermittent claudication of the extremities
- -> pain, cramping
Summarise 4 stages of a plaque?
literally, 4 words
- calcification
- rupture
- haemorrhage
- embolisation
How might fibrous plaque lead to aneurysm?
- medial layer at increased pressure due to fibrous plaque
- may provoke atrophy, loss of elastic tissue
- subsequent expansion of artery
- forming an aneurysm
Rupture or ulceration of atherosclerotic plaque would lead to…
- exposure of procoagulants within plaque circulating blood
- causing thrombus to form at site
- thrombus may occlude vessel resulting in infarction of the involved organs.
Physiological response of VSMC to hypoxia
- peripheral vessels dilatation
- BV of pulmonary vasculature constrict to
- shunting of blood from poorly ventilated region
How would myocyte constriction occur?
- inhibition of some K+ channels, which set membrane potential
- resulting depolarisation
- VG(Ca2+) channels activated
- cystolic [Ca2+] increases
- myocyte constriction.
Incase of intact endothelium. give examples of following stimuli for vasodilation?
- mechanical stimulation by increased blood flow
- catecholamines, bradykinin, platelets, released serotonin which stimulates specific receptors
what leads to the paradoxical vasoconstriction of the arterial wall?
- direct vasoconstrictor action of the stimuli on the VSMC outweighs the endothelium dependent vasodilator effect
- leads to paradoxical vasoconstriction
Diapedesis
Passage of blood cells through intact walls of the capillaries, typically accompanying inflammation
Role of macrophage foam cells
- additional source of cytokines
- e.g. effector molecules, matrix metallopeptidases 9
Describe the process of how a thrombus will finally occlude the arterial lumen
Detailed pathophysiology
- IFN-y induces macrophage matrix metallopeptidase 9 (MMP) expression
- IFN-y inhibits VSMC proliferation and collagen synthesis which further weakens the cap
- VSMC undergoes apoptosis
- After plaque ruptures the area is exposed its interior to blood
- Interior of plaque is highly thrombogenic , small molecular weight glycoprotein (tissue factor) initiates the extrinsic clotting cascade
- Tissue factor complexes with factor VII/VIIa, factor IX and X are activated
- Platelets are activated and thrombus forms quickly on the surface of a ruptured plaque
- Thrombus completely occludes the arterial lumen
- Can cause tissue necrosis , myocardial infarction or brain stroke
