18 Vascular Endothelium and Inflammation

Question 1

Q: What model describes the pathogenesis of atherosclerosis? 3 steps.

Answer 1

A: Response-to-injury Model

1. Endothelial Dysfunction (leukocyte migration)
2. Fatty-Streak Formation (foam cell formation)
3. Formation of an Advanced, Complicated Lesion of Atherosclerosis (necrotic core)

Question 2

Q: What’s the structure of blood vessels? (3-3,1,2)

Answer 2

A: Three layers (except for capillaries and venules):

Tunica intima
– Endothelium, basement membrane, (lamina propia= SM and connective T)
Tunica media
– Smooth muscle cells
Tunica adventitia
– vasa vasorum (network of small blood vessels that supply the walls of large blood vessels), nerves

Question 3

Q: What is the endothelium? formed by? (3) Role? (2)

Answer 3

A: The Endothelium is the surface separating blood from other tissues

• monolayer of endothelial cells, one cell deep (contact inhibition allows it to be 1 layer)
• Endothelial cells are very flat, about 1-2 µm thick and 10-20 µm in diameter
• Not all endothelial cells are the same (heterogeneity)

maintain health of blood vessels
regulate essential functions of blood vessels

Question 4

Q: Life of endothelial cell?

Answer 4

A: long life and have a low proliferation rate (unless new

vessels are required: angiogenesis)

Question 5

Q: What 2 types of molecules do endothelial cells produce to aid inflammation? 3 examples each.

Answer 5

A: Adhesion molecules
ICAMs
VCAM
Selectins

inflammatory mediators
IL-1,6,8
leukotrienes
MHC II

Question 6

Q: What 2 types of molecules do endothelial cells produce to aid vascular tone/permeability? Examples?

Answer 6

A: vasodilator factors
NO
prostacyclin

vasoconstricting factors
ACE
thromboxane II
leukotrienes
free radicals
endothelin

Question 7

Q: What 2 types of molecules do endothelial cells produce to aid haemostasis/thrombosis?

Answer 7

A: antithrombotic factors

procoagulant

Question 8

Q: Regulation of endothelium homeostasis. What’s resting endothelium producing? (6) what can happen? usually? What is different with atherscelorisis?

Answer 8

A: Anti-inflammatory
Anti-thrombotic
Anti-proliferative

Pro-inflammatory
Pro-thrombotic
Pro-angiogenic
(less of these 3)

can flip over and produce less of first 3 if needed
-transient and local to area where it is needed

endothelium is activated chronically for long time-> eventually gets flipped permanently

Question 9

Q: What can act as a stimulus to activate endothelium? (7) Result of an activated endothelium? (4)

Answer 9

A: Mechanical stress
Viruses
Smoking
High blood pressure
OxLDL
High glucose
Inflammation

Thrombosis Permeability
Senescence
Leukocyte recruitment
ATHEROSCLEROSIS

Question 10

Q: Endothelial dysfunction in atherosclerosis. 1. leukocyte recruitment.

When does it normally occur and what first happens to them? What happens in atherosclerosis? what aids recruitment?

Answer 10

A: during inflammation: leukocyte adhere to the endothelium of post-CAPILLARY venules and transmigrate into tissues

leukocytes adhere to activated endothelium of LARGE ARTERIES and get stuck in the subendothelial space

Newly formed post-capillary venules at the base of developing lesions provide a further portal for leukocyte entry

Question 11

Q: Describe the process of basic leukocyte recruitment and transmigration. (7)

Answer 11

A: 1. leukocytes possess receptors that have potential of binding to endothelium

2. activation of endothelium -> express needed receptors
3. binding occurs- first is weak via L selectin from leukocyte (to E/P selectin on endothelium)
4. rolling occurs
5. leukocyte becomes activated
6. activation gives ability for strong binding to endothelium (integrin from leuk and ICAM1, VCAM1 of endothelium)
7. transmigration

Question 12

Q: Describe endothelium junctions. What do they allow?

Answer 12

A: many molecules expressed that hold together = bind in homophilic way

movement through between cells without interfering with integrity of monolayer

Question 13

Q: Is the process of leukocyte recruitment essential? Where can leukocyte recruitment occur? (3) Describe.

Answer 13

A: essential for life but in atherosclerosis = damaging

physiologically it occurs in capillaries and post capillary venules and in ather. occurs in arteries

1. Capillary: endothelial cells surrounded by basement membrane and pericapillary cells (perycites)
2. Post-capillary venule: structure similar to capillaries but more pericytes (contractile cells)
3. Artery: three thick layers, rich in cells and extracellular matrix (leuk once recruited= trapped in subendothelial space)

Question 14

Q: What’s the role of endothelium in atherosclerosis? (3)

Answer 14

A: Thrombosis Permeability
Senescence
Leukocyte recruitment

Question 15

Q: Endothelial dysfunction in atherosclerosis. 2. permeability.

What lies behind the monolayer of endothelial cells in arteries?

How does endothelium activation affect permeability? Describe the process following this change.

Answer 15

A: intima= collagen and proteoglycans

Increased permeability results in leakage of plasma proteins through the junctions into the subendothelial space = trapped

1. increased perm-> LDL enter
2. lipoprotein oxidation
3. macrophage uptake
4. foam cell production
5. chronic inflammation

Question 16

Q: Endothelial dysfunction in atherosclerosis. 3. blood flow.

How does blood flow affect endothelial function in terms of atherosclerosis? WHY? (2)

Answer 16

A: 1. atherosclerosis does not occur uniformly
2. tends to occur at branch points as blood flow here is turbulent

1. endothelium exposed to laminar flow produces athero-protective molecules= activate athero-protective pathways (antithrombotic and anti inflammatory) eg KLF2, 4
2. endothelium phenotype exposed to turbulent flow becomes athero prone-> certain pathways (thrombotic and inflammatory) are activated= create an atherosclerosis susceptible region

Question 17

Q: Compare laminar flow and disturbed flow. (2,2) When do you get turbulent flow?

Answer 17

A: Laminar flow
– Streamlined
– Outermost layer moving slowest and centre moving fastest

Disturbed flow (turbulent)
– Interrupted
– Rate of flow exceeds critical velocity

Fluid passes a constriction, sharp turn, rough surface

Question 18

Q: What does laminar flow promote? (4) Disturbed, turbulent flow? (3)

Answer 18

A: Laminar blood flow promotes:

• anti-thrombotic, anti-inflammatory factors
• endothelial survival
• Nitric oxide (NO) production** important
• Inhibition of SMC proliferation

Disturbed blood flow promotes:

• coagulation, leukocyte adhesion, SMC proliferation
• endothelial apoptosis
• Loss of Nitric oxide (NO) production**

Question 19

Q: What is epigenetics? 3 key mechanisms? Relevance? What can regulate epigenetics?

Answer 19

A: functionally relevant, inheritable changes to the genome that do not involve a change in the nucleotide sequence, which affect gene expression

• DNA methylation
• Histones modifications
• miRNA

said pathways can be targets for drugs

flow (in endo cells)

Question 20

Q: How does blood flow control epigenetics in endothelial cells?

Answer 20

A: laminar flow downregulates expression of DNA
methyltransferases (DNMTs), which allows the promoter
of antiatherogenic genes, such as Klf4 and HoxA5, to
remain demethylated, enabling their expression.

Disturbed flow upregulates DNMT expression,
leading to hypermethylation of the promoter of
antiatherogenicgenes, such as Klf4 and HoxA5,
repressing their expression

when expression of them is repressed you get pro atherogenesis

• apoptosis EC
• proliferation SMC
• inflammation
• thrombosis

Question 21

Q: Endothelial dysfunction in atherosclerosis. 4. angiogenesis.

What is angiogenesis? Triggered by?

Answer 21

A: Formation of new blood vessels by sprouting from

pre-existing vessels = cascade of events triggered by need for blood/oxygen = HYPOXIA TRIGGERS

Question 22

Q: What’s the role of angiogenesis in CVD?

Answer 22

A: JANUS PARADOX

can be detrimental to atherosclerosis and CVD but also beneficial

Question 23

Q: How can angiogenesis be detrimental in CVD? (3)

Answer 23

A: -when you have a large plaque-> leads to hypoxic environment-> produces pro atherogenic

• get angiogenesis
• this then aids plaque growth-> as the new blood vessels are exposed to the same stimuli that allowed plaque formation = can contribute to growth of plaque

Question 24

Q: How can angiogenesis be beneficial in CVD? Give an example and describe.

Answer 24

A: -therapeutic angiogenesis prevents damage post ischaemia
- eg acute occlusion of coronary = acute interuption of blood flow = downstream tissue is deprived of oxygen = dies (infarction) = tisssue is fibrotic and unable to function as a pump -> could get heart failure
-solution given: was to deliver growth factors/stem cells to the ischemic heart region to induce new vessel
growth (fast enough to prevent death of tissue)

Question 25

Q: Endothelial dysfunction in atherosclerosis. 5. senescence.

What is cellular senescence? Describe senescent cells. Specific marker?

Answer 25

A: growth arrest that halts the proliferation of ageing and/or damaged cell - have distinctive morphology and acquire specific markers, e.g. b-gal

Question 26

Q: Why is senescence good? (2) Bad?

Answer 26

A: Good: prevents the transmission of damage to daughter cells (prevents damaged cell growth)
– Replicative senescence: the limited proliferative capacity of human cells in culture
– Senescence as response to stress and damage

Not so good: senescent cells are pro-inflammatory and contribute to many diseases

Question 27

Q: What can induce endothelial cell senescence? Where are senescent endothelial cells found? What’s their phenotype and what can they contribute to?

Answer 27

A: CV risk factors, such as oxidative stress

atherosclerotic lesions

pro-inflammatory and prothrombotic phenotype and therefore may contribute to atherosclerosis plaque progression and its complications

Question 28

Q: What’s the fate for a atherogenic plaque? (2)

Answer 28

A: rupture or be stabilised by fibrous cap

Question 29

Q: How to protect the endothelium and prevent atherosclerosis?

Answer 29

A: promoting protective pathways (Anti-inflammatory, Anti-thrombotic, Anti-proliferative) or inhibiting inflammatory ones (Pro-inflammatory, Pro-thrombotic, Pro-angiogenic)

difficult to inhibit ^