9. Vascular endothelium 2

Question 1

What are the 3 layers of blood vessel walls and what is contained in each layer?

Answer 1

Tunica intima: endothelial cells
Tunica media: smooth muscle cells
Tunica adventitia: vasa vasorum and nerves

Question 2

Vaso vasorum

Answer 2

small blood vessels that supply the walls of large blood vessels

Question 3

List 4 critical functions endothelial cells are involved in

Answer 3

Inflammation
Vascular Tone and Permeability
Angiogenesis
Thrombosis and Haemostasis

Question 4

A common way endothelial cells controls processes

Answer 4

Control many processes by keeping a balance between pro and anti

Question 5

Various stimuli can chronically activate the endothelium

Answer 5

After many years of this stimuli, the balance becomes tilted permanently on the activated side
This promotes atherosclerosis

Question 6

10 agents that can chronically activate the endothelium

Answer 6

Hypertension
Hypercholesterolemia 
Diabetes mellitus
Sex hormone imbalance
Ageing
Oxidative stress
Proinflammatory cytokines
Infections agents
Environmental toxins e.g. cigarette smoke
Haemodynamic forces e.g. disturbed blood flow

Question 7

When and where does leukocyte recruitment normally take place? Why does this normal recruitment of leukocytes not cause atherosclerosis?

Answer 7

During inflammation
Post-capillary venules
Normally, the leukocytes transmigrate into tissues

Question 8

What happens to leukocytes when they adhere to activated endothelium of large arteries?

Answer 8

They get stuck in the subendothelial space
Newly formed post-capillary venules at the base of developing lesions provide a further portal for leukocyte entry
Monocytes migrate into the subendothelial space differentiate into macrophages

Question 9

How are the large vessels different to the post-capillary venules?

Answer 9

Beyond the endothelium there is a THICK layer which the leukocytes cannot get through
So they get stuck in the sticky subendothelial space and accumulate there

Question 10

Briefly describe leukocyte recruitment.

Answer 10

Leukocytes have weak interactions via selectins.
When the endothelium is activated, it will express chemokines that bind to receptors on the leukocytes and switches their integrins to the high affinity state and subsequent binding to its ligand on the endothelial cells. This allows leukocyte immobilisation on the endothelial surface and transmigration.

Question 11

What activates the endothelium?

Answer 11

An inflammatory trigger

Question 12

Describe the development and life of endothelial cells

Answer 12

Endothelial cells grow next to each other (not 3D) because of contact inhibition (when 2 growing cells touch, they engage with molecular pathways that “say” stop proliferating)
Endothelial cells don’t divide much and have a long life.
There are junctions between endothelial cells (which leukocytes can squeeze through)

Question 13

Describe the structure of a capillary

Answer 13

endothelial cells surrounded by basement membrane and pericapillary cells (pericytes)
The BM is thin so leukocytes can get through.

Question 14

How does a post-capillary venue differ to a capillary?

Answer 14

Structure similar to capillaries but more pericytes

Question 15

What does Increased endothelial permeability result in?

Answer 15

Leakage of plasma proteins through the junctions into the subendothelial space.
Can lead to swelling (Oedema)

Question 16

What happens to lipoproteins that pass through the activated endothelium?

Answer 16

Lipoproteins bind to proteoglycans and get oxidised

Macrophages that have passed through “gobble up” lipoproteins: this forms foam cells and “fatty streaks”

Question 17

Where do Atherosclerotic plaques form preferentially and why?

Answer 17

At branch points
In a bend/narrowing flow becomes turbulent
Endothelial cells sense flow and their transcription factors are activated by type of flow

Question 18

List 4 protective effects of LAMINAR FLOW

Answer 18

Promotion of:
Antithrombotic factors
Anti-inflammatory factors
NO production
Inhibition of SMC proliferation

Question 19

List 5 negative effects of TURBULENT FLOW

Answer 19

Promotion of:
Coagulation
Leukocyte adhesion
SMC proliferation
Endothelial apoptosis 
Reduced NO production

Question 20

6 protective effects of nitric oxide (NO)

Answer 20

Dilates blood vessels
Reduces platelet activation
Inhibits monocyte adhesion
Reduces proliferation of SMC in the vessel wall
Reduces release of superoxide radicals
Reduces oxidation of LDL cholesterol (major component of plaque)

Question 21

Which endothelial transcription factors are activated in laminar and turbulent flow?

Answer 21

Laminar: KLF2 and KLF4; anti-inflammatory, anti-thrombotic
Turbulent: NF-KB; pro-inflammatory, pro-thrombotic

Question 22

3 key epigenetic mechanisms

Answer 22

DNA methylation
Histones modifications
miRNA

Question 23

Blood flow regulates endothelial epigenetic pathways, mechanoreceptors sense blood flow, resulting in changes in chromatin

Answer 23

Stable flow: downregulates expression of DNA methyltransferases (DNMTs), which allows the promoter of antiatherogenic genes, e.g. Klf4 and HoxA5, to remain demethylated, enabling their expression.

Disturbed flow (d-flow) upregulates DNMT expression, leading to hypermethylation of the promoter of antiatherogenic genes, e.g. Klf4 and HoxA5, repressing their expression.

Question 24

Angiogenesis

Answer 24

The formation of new blood vessels by sprouting from pre-existing vessels.

Question 25

What 3 processes is angiogenesis essential for?

Answer 25

Embryonic development
Menstrual cycle
Wound healing

Question 26

What environmental factor can cause angiogenesis?

Answer 26

Hypoxia induces production of growth factors causing growth of new blood vessels

Question 27

Why is angiogenesis, in the context of cardiovascular disease, related to the Janus paradox?

Answer 27

BAD for atherosclerosis: an advanced plaque has a lot of necrotic debris inside and there is hypoxia: stimulates angiogenesis from vasa vasorum (fragile): more leukocytes enter and contribute to the growth of the plaque
GOOD for myocardial infarction: therapeutic angiogenesis could reoxygenate ischaemic tissue downstream of an occlusion, preventing tissue damage and heart failure

Question 28

What is cell senescence?

Answer 28

Growth arrest that halts the proliferation of ageing and/or damaged cells
Senescent cells have distinctive morphology and acquire specific markers (e.g. b-gal)

Question 29

Benefits of cell senescence

Answer 29

Protective against cancer because it prevents damaged cells from proliferating

Question 30

Replicative senescence

Answer 30

the limited proliferative capacity of human cells in culture

Question 31

What is the problem with cell senescence?

Answer 31

Senescent cells are pro-inflammatory and contribute to may diseases

Question 32

Atherosclerosis and endothelial senescence

Answer 32

Senescent endothelial cells are found in atherosclerotic lesions (induced by cardiovascular risk factors (e.g. oxidative stress))
Senescent cells have a proinflammatory and prothrombotic phenotype, therefore may contribute to atherosclerosis plaque progression and its complications

Question 33

What cardiovascular benefits are given by resveratrol in red wine?

Answer 33

Prevents pro-inflammatory changes induced by a high fat meal in leukocytes
Improves endothelial function in Obese T2DM

Question 34

Hormetic action of resveratrol

Answer 34

beneficial effects at lower doses

cytotoxic effects at higher doses

Question 35

List 3 factors that can promote vascular health

Answer 35

Diet
Exercise
Statins

Question 36

Describe the formation of an atherosclerotic plaque

Answer 36

Chronic stimulation of large vessels causes endothelial activation
Permeability increases
Leukocytes attach and migrate through
Lipids also pass through, bind to proteoglycans, get oxidised and accumulate
Macrophages engulf lipids forming foam cells and fatty streaks
Formation of a necrotic core
Over time a complex atherosclerotic plaque forms