CVS 18 - Vascular Endothelium

Question 1

Describe the basic structure of blood vessels. (3 Layers)

Excluding capillaries and venules

Answer 1

1. Tunica Intima (innermost)
2. Tunica Media (SMC)
3. Tunica Adventitia (vasa vasorum, nerves)

Question 2

Endothelia are monolayeric. How?

Answer 2

When endothelial cells divide they exhibit contact inhibition.

Question 3

What are the critical functions of endothelial cells?

Answer 3

1. Inflammation
2. Vascular tone and permeability
3. Angiogenesis
4. Thrombosis and haemostasis

Question 4

Describe how endothelia can become permanently activated.

Answer 4

When healthy, endothelial cells are in an anti-inflammatory, anti-thrombotic state.

If activated (e.g. by cutting yourself), endothelial become activated and switch to a pro-inflammatory, pro-thrombotic, pro-angiogenic state.

In atherosclerosis, chronic number of stimuli (smoking, high BP, etc) means that the endothelia are ALWAYS activated so it doesn’t flip back to normal state.

Question 5

What happens to leukocytes that in atherosclerosis?

Answer 5

They adhere to the activated endothelium of large arteries - they get stuck in sub endothelial space.

Question 6

Explain how leukocytes are recruited and bind to the endothelial cells.

Answer 6

1. Leukocyte molecules interact with the endothelium but are usually switched off.
2. Some, e.g. selectins, are switched on but they don’t have a binding partner on the endothelial cell.
3. However, when endothelial cell is activated (inflammation occurs), the endothelium expresses ligands for the leukocytes.
4. Selectin binding - rolling
5. Signals activate integrin into high affinity state.
6. Integrins then strongly bind to ligands on endothelium.

Question 7

Which protein is present at endothelial junctions?

Answer 7

V-cadherin

Question 8

How do endothelial cells allow things to go through it?

Answer 8

At endothelial junctions, there are cell membrane proteins that bind to each other in a homophilic way.

The homophilic binding creates a zipper, which can zip and unzip to allow things to pass through.

Question 9

Why is transmigration a problem in atherosclerosis (venules vs arteries).

Answer 9

Leukocyte transmigration occurs in post-capillary venules. But the venules only have endothelial cells, basement membrane and pericapillary sites. So the leukocyte can chew through the basement membrane using enzymes and pass into tissue.

If a leukocyte adheres to inside of coronary artery/aorta, the enzymes cannot pass through the big thick layer - this is how atherosclerosis starts.

Question 10

Activated endothelia have increased permeability. What are the consequences of this?

Answer 10

Increased permeability = leakage of plasma proteins through endothelial junctions into sub endothelial space.

Question 11

What is present directly below the endothelium?

Answer 11

Layer of sticky molecules - collagen and proteoglycan.

Question 12

Where does atherosclerosis tend to occur? Why?

Answer 12

At branch points. Because there is turbulent flow present at these points.

Question 13

Contrast the effects of laminar flow and turbulent flow.

Answer 13

Laminar flow = positive protective signal (triggers production of protective molecules e.g. NO)

Turbulent Flow = activtaes inflammatory and thrombotic pathways (opposite effect of laminar flow)

Question 14

Name 3 things that laminar blood flow promotes

Answer 14

1. NO production
2. Factors inhibiting coagulation, leukocyte adhesion, SMC proliferation
3. Endothelial survival

Question 15

Name 2 things that turbulent flow promotes

Answer 15

1. Coagulation, leukocyte adhesion, SMC proliferation

2. Endothelial apoptosis

Question 16

What is angiogenesis?

Answer 16

The formation of new blood vessels by sprouting from preexisting vessels.

Totally controlled by endothelial cells, and it is triggered for a need for oxygen or perfusion (hypoxia).

More relevant to disease (e.g. cancer)

Question 17

How may epigenetics affect atheroma formation?

Demethylation = activation

Answer 17

Stable flow down regulates DNMTs, which allows expression of anti-atherogenic genes.

(opposite effect for disturbed flow)

Question 18

Explain the Janus paradox of angiogenesis.

Answer 18

1. Negative = advanced plaques are hypoxic. Hypoxia stimulates vasa vasorum (tunica adventitia) angiogenesis. But these vasa vasorum vessels are leaky and fragile and stimulates leukocytes to come in and contribute to atherosclerotic growth.
2. Positive = interventional cardiologists believe that if we can act really quickly after an MI, we can reoxygenate the myocardium downstream of an occlusion using therapeutic angiogenesis, preventing heart failure.

Question 19

What is senescence?

Answer 19

Growth arrest which inhibits the proliferation of aged/damaged cells

Protective mechanism against cancer

Question 20

What are the good and bad things about senescence?

Answer 20

Good - prevents damage transmission to daughter cells

Bad - senescent cells are pro inflammatory and can contribute to diseases (e.g. atherosclerosis)

Question 21

How can endothelial senescence be induced?

Answer 21

By cardiovascular RFs such as oxidative stress

Question 22

What is resveratrol and why is it good?

Answer 22

Red wine contains resveratrol - which has anti-inflammatory properties on the endothelium.

Red wine has a hermetic action - beneficial at lower doses but cytotoxic at higher doses.

Question 23

Where does leukocyte transmigration occur physiologically?

Answer 23

In post capillary venules.