Artherogenesis, artherosclerosis and endothelial cells Flashcards
1. Describe the cellular and metabolic mechanisms of artherogenesis 2. Describe the critical role of endothelial cell function in understaning vascular homeostasis and endothelial dysfunction as an early step in the sequence of artherogenesis 3. Describe how basic processes of artherogenesis directly impact on clinical syndromes and current treatments
Artherosclerosis -definition
Hardening, thickening and loss of elasticity of the artery wall
Artherofibroma
Arteriosclerosis with prominent fatty and fibrous components
Artherothrombosis
Arteriosclerosis with prominent fatty and thrombotic components
Features of atherogenesis
- Chronic inflammatory process (maladaptive response to injuy)
- Long term developement -may begin as early as late teens but clinical presentation is usually decades later
- Some disease processes are slow (lipid accumulation) and some are fast (thrombosis) each process can be major or minor in amplitude.
- Diffuse disease with focal predilection (especially in the arteries with many branch points where flow turbulence can occur - focal predilections will determine what symptoms are present)
- Endothelial cell layer forms interface between blood and arterial wall and therefore critical to disease
Structure of normal artery
- three layers: tunica intima, media and adventitia
- three layers surround lumen (containing blood))
- in between layers = elastic lamina (internal and external)
Tunica intima composition
endothelial cells
internal elastic lamina
Tunica media composition
- smooth muscle cells
- extracellular matrix (produced by SMC)
- external elastic lamina
Tunica adventia composition
- vasa vasorum (penetrating small vessels that feed the artery)
- nerve endings that supply the arteriole wall
Function of the endothelial cells - role in maintaining normal arterial function (4)
a) tight junctions = barrier protecting subendothelial space from blood-borne elements (white cells, lipids)
b) normal flow (shear stimulation) helps keep the endothelial cells functioning normally (to maintain a antithrombotic and non-adherent surface and relatively relaxed SMC with low propensity to synth extracellular matrix and low propensity to replicate or migrate)
c) produces antioxidants that scavenge free radicals (ex superoxide dismutase)
d) under normal conditions is a suppresion of endothelial cell capacity to elaborate receptors that can bind WBC to its surface + suppression of its capacity to elaborate mediators of SMC constriction (endothelin)
Importance of normal laminar flow (2)
- normal laminar flow provides high shear stress stimulation across the surface of the endothelial cell
- endothelial cells change shape in response to flow and align themselves to the direction of flow
- shear stress also induces activity of NO system a key pathway in maintaining normal vascular function (does so by upregulating nitric oxide synthase enzyme that converts L-arg to NO)
a) Role of smooth muscle cell in normal arterial function (what do to + 2 net effects)
b) Suppression of what smooth muscle cell functions are critical to vascular homeostasis
a) -serves to modulate size (blood carrying capacity) of the artery
- to meet metabolic demand and maintain normal tissue perfusion pressure
b) suppression of smooth muscle cell replication, migration and synthetic capacities is critical for vascular homeostasis
Role of extracellular matrix in smooth muscle cell in normal arterial function
-helps provide structural integrity in face of pressurized blood and pulsatile pressure variation
Location, and origin of extracellular matrix
- mainly in the medial layer
- produced by a low basal level of SMC synthetic function
a) Composition of extracellular marix
b) function of collagen
- fibrillar collagen provides the strength
- proteoglycans and elastin provide the flexibility
b) collagen inhibits SMC growth and preserves SMC longevity by making them less likely to undergo apoptosis
Why does atherogenesis begin (overall + types -2)
- a response to injury hypothesis
- assaults on the endothelium that promote creation of superoxide radicals which further assault endothelial cell and can initiate other adverse processes
- ultimately leading to endothelial dysfunction
- many agents of injury:
a) physical forces (hemodynamic stress at branch points leading to turbulent flow, barotrauma of hypertension)
b) chemical irritants (tobacco smoke, excess lipids or glucose)
Steps to intial inflammatory response in generation of atherosclerosis
1) Noxious stimuli (physical or chemical) injures the endothelium
2) Leads to elaboration of leukocyte adhesion molecules (VCAM-1, ICAM-1, E-selectin, P-selectin) and chemotractants (MCP-1, IL-8, interferon inducible protein 8)
3) monocytes and T-lymphocytes adhere
4) Diapedesis of white cells between endothelial cells allowing white cells to get into subendothelial space
5) Monocytes become macrophages and express scavenger receptor (foam cell) –” macrophage engorges itself with modified LDL (since scavenger receptor has no feedback mechanism) which contains cholesterol and cholesteryl ester. Eventually foam cells die and form cholesterol crystals (forming the necrotic cholesterol core of atherosclerosis = dead, or dying foam cells, extracellular cholesterol and extracellular cholesterol crystals)
Action of immune cells (specifically monocytes/macrophage) in subendothelial space
- monocytes become macrophage FOAM CELLS
- these produce many inflammatory cytokines and chemoattractants
- foam cells have scavenger receptors that are unregulated (take up foreign body - modified LDL to the point of self destruction - no regulation of digestion)
- foam cell self-destructs and releases cholesterol/crystals that further enhance inflammation
Action of dendritic cells or antigen-presenting cell in inflammatory/immune response
- presents antigens to T-cells and B cells
- forms a bridge between innate and adaptive immunity
1) activated T cells produce Th1 cytokines that further activate macrophages and vascular cells
2) Some of the activated T cells are regulatory T cells - produce anti-inflammatory cytokines such as IL-10 and TGF-beta
3) Beta cell activation
Focus on alteration of subendothelial space
- lipids are trapped in the subendothelial space by proteoglycans where they are rendered prone to modification (mLDL -either oxidative modification of glycation which occurs in the presence of glucose)
- mDL is directly toxic to the endothelium and to SMCs and contribute to the transformation that these two cells undergo
- mLDL induce further leukocyte recruitment and inflammatione thereby increase number macrophages
- mLDL can induce autoantibody formation (antibodies to oxidized LDL) further aggravating local inflammation
time in residence phenomenon
- due to stickiness of subendothelial space (because of proteoglycans)
- once things are in subendothelial space are hard to get out and more time/chance that they will interact with each other
- promotes modified LDL interacting with foam cells
- induces further leukocyte recruitment - thereby perpetuating ifoam cell formation and interacting with LDL –> MORE INFLAMMATION
Normal function of smooth muscle cells
- relaxed
- non-migratory
- non-replicating
- low/basal level synthetic function for elaboration of ECM
Smooth muscle cell changes with onset of endothelial cell dysfunction
1) endothelium produces more contractile mediators (endothelin, angiotensin II)
2) these percolate down and affect SMC
+ vasodilatory mediators (prostacyclin, NO) are diminished/destroyed by free radicals (inflammatory milleu)
Net effect on SMC :
a) more contracted
3) In response undergo cellular and metabolic changes favoring:
a) synthesis of excess ECM
b) replication
c) migration to subendothelial space
d) production of free radicals
e) remodeling of entire artery
Extracellular matrix contribution to artherogenesis
- SMC produces excessive amount of ECM
- ECM enhances stickiness/trapping feature of subendothelial space
- amount/type of ECM produced will also affect arterial remodelling
Vasa vasorum contribution to artherogenesis
- proliferate and grow towards the developing plaque
- provide another conduit for WBC and cholesterol
- fragile and prone to hemorrage that can lead to:
a) expansion of growing plaque
b) heme deposit that can lead to oxidized state in already inflamed plaque
c) RBC disintegration have alot of lipid in membrane = another source of cholesterol in the plaque
How thrombosis occurs during artherogenesis
1) endothelial cell becomes less resistant to platelet aggregation/thrombin formation early on
2) platelet/thrombbin complex may be incorporated into growing plaque
3) Growing plaque contains tissue factor and PAI-1 - both which are highly thrombogenic - if plaque ruptures and exposes these mediators to the circulating blood is a very strong stimulus for thrombosus formation
Positive/compensatory remodelling
- aka glagov effect
- adaptive mechanism to maintain normal lumen size even when plaque is accumulating
- maintains because outer muscular wall has outwardly remodelled to preserve lumen size
- can only proceed to certain extent –> eventually too much atheleroma for remodelling to accomodate and eventually get luminal steonosis
Non-compensatory /negative remodelling
- remodelling isn’t always positive
- contributes to luminal narrowing
- still unclear why one part of artery will respond with compensatory and other non-compensatory remodelling
2 main ways of plaque formation
1) Stabilized plauque
2) Vulnerable plaque
Properties of stabilized plaque (3)
- small lipid pool
- thick fibrous cap
- preserved lumen –> over time lumen will narrow = leading to exertional angina
Properties of vulnerable plaque (3) + what happens if break occurs
- thin fibrous cap (vulnerable to breakage)
- large lipid pool
- many inflammatory cells (foam cells, mediators protein degredation)
- if break occurs thrombotic tissue factor and PAI-1 cause thrombosis which can lead to accute coronary syndrome – > myocardial infarction
- healed ruptured plaque wiill have a very narrow lumen = exertional angina
Difference in process atherogenesis that gives vulnerable vs. stable plaque
- relates to balance of process that favor lipid accumulation and inflammation (promting thin cap fibroatheroma) vs. those that favor smc replication and matrix synthesis (promoting thick cap fibroatheroma)
- overall poorly understood
Classical feaatures of a vulnerable plaque “thin-cap fibratheroma=TCFA (4)
- large lipid/necrotic core
- few SMC (thin fibrous cap and little ECM)
- Many foam cells -especially in shoulder region (contribute to structural weakness and produce MMP)
- The amount of plaque is generally substantial even though the lumen may be only midly or moderately stenotic *due to remodelling
Mechanism of acute coronary thrombosis
1) Rupture of TCFA = typical mechanism
2) Erosion - erode surface without rupture and end up with thrombus (more common in women and hypertensive patients)
3) Cap destabilized by calcified nodule in cap leading to vulnerability for rupture
How ASA manages atherosclerosis
-reduced platelet reactivity
How statins manage atherosclerosis
- reduction of # of LDL particles;
- reduced foam cells
- improved endothelial function
How smoking cessation manages atherosclerosis
- reduced ox-LDL
- decreased platelet reactivity
- reduced sympathetic constriction of SMC
- improved endothelial function
How antihypertensives manage atherosclerosis
- decreased endothelial cell and SMC barotrauma
- reductin of SMC production of oxidized free radicals
- improved endothelial function
How diabetes therapy manages artherosclerosis
-reduction of irritating glycated products such as glycated LDL
How exercise manages atherosclerosis
- increased blood flow
- increased shear stimulation of endothelial cells
Atherogenesis
General term for the processes leading to the creation of atherosclerosis
What layers of the vascular wall does atherosclerosis affect
Mainly the intima, but all regions of the vascular wall (intima, internal elastic lamina, media, external elastic lamina and adventia) can be affected
-all elements making up these regions participate in the process (endothelial cells, smooth muscle cells, extra-cellular matrix)
Where is atherosclerosis first classically seen
In the dorsal aspect of the abdominal aorta, then the proximal coronaries, the popliteal arteries, the descending thoracic aorta, the interanl carotids and then finally the renal arteries
What does normal endothelium regulate (6)
1) Transport of substances into and out of the subendothelial space
2) Thrombosis
3) White cell adhesion
4) Vasomotion of vascular SMC
5) Growth and apoptosis of vascular smc in the media
6) Oxidative state
What is endothelial dysfunction characterized by
1) Altered permeability
2) prothrombotic state on vessel surface
3) White cell adhesion receptors on surface
4) inadequate vasodilation
5) increased secretion of growth factors
6) increased oxidative state
Besides dendritic cells what is another mechanism by which the adaptive immune system becomes activated
mLDL and other modified elements may induce antibodies (Ab to oxidized LDL) that contribute to the immune and inflammatory response
