Artherogenesis, artherosclerosis and endothelial cells

Question 1

Artherosclerosis -definition

Answer 1

Hardening, thickening and loss of elasticity of the artery wall

Question 2

Artherofibroma

Answer 2

Arteriosclerosis with prominent fatty and fibrous components

Question 3

Artherothrombosis

Answer 3

Arteriosclerosis with prominent fatty and thrombotic components

Question 4

Features of atherogenesis

Answer 4

1. Chronic inflammatory process (maladaptive response to injuy)
2. Long term developement -may begin as early as late teens but clinical presentation is usually decades later
3. Some disease processes are slow (lipid accumulation) and some are fast (thrombosis) each process can be major or minor in amplitude.
4. 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)
5. Endothelial cell layer forms interface between blood and arterial wall and therefore critical to disease

Question 5

Structure of normal artery

Answer 5

• three layers: tunica intima, media and adventitia
• three layers surround lumen (containing blood))
• in between layers = elastic lamina (internal and external)

Question 6

Tunica intima composition

Answer 6

endothelial cells

internal elastic lamina

Question 7

Tunica media composition

Answer 7

• smooth muscle cells
• extracellular matrix (produced by SMC)
• external elastic lamina

Question 8

Tunica adventia composition

Answer 8

• vasa vasorum (penetrating small vessels that feed the artery)
• nerve endings that supply the arteriole wall

Question 9

Function of the endothelial cells - role in maintaining normal arterial function (4)

Answer 9

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)

Question 10

Importance of normal laminar flow (2)

Answer 10

• 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)

Question 11

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

Answer 11

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

Question 12

Role of extracellular matrix in smooth muscle cell in normal arterial function

Answer 12

-helps provide structural integrity in face of pressurized blood and pulsatile pressure variation

Question 13

Location, and origin of extracellular matrix

Answer 13

• mainly in the medial layer

- produced by a low basal level of SMC synthetic function

Question 14

a) Composition of extracellular marix

b) function of collagen

Answer 14

• 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

Question 15

Why does atherogenesis begin (overall + types -2)

Answer 15

• 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)

Question 16

Steps to intial inflammatory response in generation of atherosclerosis

Answer 16

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)

Question 17

Action of immune cells (specifically monocytes/macrophage) in subendothelial space

Answer 17

• 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

Question 18

Action of dendritic cells or antigen-presenting cell in inflammatory/immune response

Answer 18

• 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

Question 19

Focus on alteration of subendothelial space

Answer 19

• 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

Question 20

time in residence phenomenon

Answer 20

• 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

Question 21

Normal function of smooth muscle cells

Answer 21

• relaxed
• non-migratory
• non-replicating
• low/basal level synthetic function for elaboration of ECM

Question 22

Smooth muscle cell changes with onset of endothelial cell dysfunction

Answer 22

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

Question 23

Extracellular matrix contribution to artherogenesis

Answer 23

• SMC produces excessive amount of ECM
• ECM enhances stickiness/trapping feature of subendothelial space
• amount/type of ECM produced will also affect arterial remodelling

Question 24

Vasa vasorum contribution to artherogenesis

Answer 24

• 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

Question 25

How thrombosis occurs during artherogenesis

Answer 25

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

Question 26

Positive/compensatory remodelling

Answer 26

• 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

Question 27

Non-compensatory /negative remodelling

Answer 27

• 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

Question 28

2 main ways of plaque formation

Answer 28

1) Stabilized plauque

2) Vulnerable plaque

Question 29

Properties of stabilized plaque (3)

Answer 29

• small lipid pool
• thick fibrous cap
• preserved lumen –> over time lumen will narrow = leading to exertional angina

Question 30

Properties of vulnerable plaque (3) + what happens if break occurs

Answer 30

• 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

Question 31

Difference in process atherogenesis that gives vulnerable vs. stable plaque

Answer 31

• 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

Question 32

Classical feaatures of a vulnerable plaque “thin-cap fibratheroma=TCFA (4)

Answer 32

1. large lipid/necrotic core
2. few SMC (thin fibrous cap and little ECM)
3. Many foam cells -especially in shoulder region (contribute to structural weakness and produce MMP)
4. The amount of plaque is generally substantial even though the lumen may be only midly or moderately stenotic *due to remodelling

Question 33

Mechanism of acute coronary thrombosis

Answer 33

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

Question 34

How ASA manages atherosclerosis

Answer 34

-reduced platelet reactivity

Question 35

How statins manage atherosclerosis

Answer 35

• reduction of # of LDL particles;
• reduced foam cells
• improved endothelial function

Question 36

How smoking cessation manages atherosclerosis

Answer 36

• reduced ox-LDL
• decreased platelet reactivity
• reduced sympathetic constriction of SMC
• improved endothelial function

Question 37

How antihypertensives manage atherosclerosis

Answer 37

• decreased endothelial cell and SMC barotrauma
• reductin of SMC production of oxidized free radicals
• improved endothelial function

Question 38

How diabetes therapy manages artherosclerosis

Answer 38

-reduction of irritating glycated products such as glycated LDL

Question 39

How exercise manages atherosclerosis

Answer 39

• increased blood flow

- increased shear stimulation of endothelial cells

Question 40

Atherogenesis

Answer 40

General term for the processes leading to the creation of atherosclerosis

Question 41

What layers of the vascular wall does atherosclerosis affect

Answer 41

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)

Question 42

Where is atherosclerosis first classically seen

Answer 42

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

Question 43

What does normal endothelium regulate (6)

Answer 43

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

Question 44

What is endothelial dysfunction characterized by

Answer 44

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

Question 45

Besides dendritic cells what is another mechanism by which the adaptive immune system becomes activated

Answer 45

mLDL and other modified elements may induce antibodies (Ab to oxidized LDL) that contribute to the immune and inflammatory response