vascula endothelium 2

Question 1

what do endothelial cells do?

Answer 1

inflammation
angiogenesis
thrombosis and haemostasis
vascular tone ad permeability

Question 2

endothelial cell dysfunction in atherogenesis: stimuli

Answer 2

hypercholesteraemia 
daibetes mellitus 
hypertension 
sex hormone imbalance 
ageing 
oxidative stress
proinflammatory cytokines
infectious agents 
environmental toxins 
haemodynamic forces

Question 3

aside from large arteries and post capillary venules, what other venules can provide a further portal for leukocyte entry

Answer 3

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

Question 4

monocytes migrate into the subendothelial space and differentiate into

Answer 4

macrophages

Question 5

how do the endothelial junctions allow things to go through without the whole endothelium falling apart

Answer 5

Leukocytes transmigrate by squeezing through endothelial junctions

At the junctions, two endothelial cells are very close to each other and the cell membrane proteins on each cell bind in a homophilic way

This binding of membrane proteins creates a zipper

The junctions can zip and unzip to allow things to go through without the whole endothelium falling apart

Question 6

Define capillary

Answer 6

Capillary: endothelial cells surrounded by basement membrane and pericapillary cells (pericytes)

Question 7

Define post capillary venule:

Answer 7

Post-capillary venule: structure similar to capillaries but more pericytes

Question 8

Define artery

Answer 8

Artery: three thick layers, rich in cells and extracellular matrix

Question 9

vascular endothelium function and what happens when there is increased permeability

Answer 9

The endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa
Increased permeability results in leakage of plasma proteins through the junctions into the subendothelial space

Question 10

what happens in lipoprotein trapping and oxidative modification

Answer 10

When the endothelium becomes activated, the cholesterol goes under the endothelial layer

The LDLs then get modified as it is a very oxidative environment

The LDLs then get stuck in the subendothelial layer

The macrophages then come and phagocytose the LDLs forming FOAM CELLS

This is the source of the chronic inflammation

Question 11

why does atherosclerosis occur at branch points?

Answer 11

Atherosclerosis is not evenly distributed across the vasculature, it tends to occur at BRANCH POINTS

This is because you get turbulent flow at branch points

Laminar flow can be sensed by the endothelium as a positive protective signal - this means that it triggers the production of a lot of protective molecules e.g. nitric oxide

Turbulent flow triggers the balance to go the other way and activates the inflammatory and thrombotic pathways

Question 12

what happens in laminar flow?

Answer 12

Streamlined, outermost layer moving slowest and centre moving fastest

Question 13

what happens in turbulent flow?

Answer 13

Irregular flow

Speed of fluid is continuously undergoing changes in both magnitude and direction

Question 14

protective effects of laminar flow

Answer 14

Laminar blood flow promotes antithrombotic factors, anti-inflammatory factors, nitric oxide production, inhibition of SMC proliferation

Question 15

detrimental effects of turbulent flow

Answer 15

Disturbed blood flow promotes coagulation, leukocyte adhesion,
SMC proliferation,
endothelial apoptosis reduced nitric oxide production

Question 16

give examples of protective effects of nitric oxide on vascular endothelium

Answer 16

reduces oxidation of LDL cholesterol 
dilates blood vessels 
reduces platelet activation 
inhibits monocyte adhesion 
reduces proliferation of SMC in the vessel wall
reduces release of superoxide radicals

Question 17

blood flow patterns determine susceptibility to atherosclerosis

Answer 17

Early lesions of atherosclerosis in the human carotid artery develop in the area of a major curvature (carotid sinus) exposed to low time-average shear stress, a high oscillatory shear index, and steep temporal and spatial gradients. Endothelial cells at this site display an atheroprone phenotype, which promotes a proinflammatory milieu driven by the priming of the NF-κB signaling pathway, which is then perpetuated in response to subendothelial apoB LPs. NF-κB activation promotes the entry of blood-borne monocytes (blue cells) through the junctions of endothelial cells (orange cells) into the intima, and there, monocytes differentiate into macrophages (red cells). In contrast, arterial geometries that are exposed to uniform laminar flow evoke an atheroprotective endothelial cell phenotype driven by the transcriptional integrators KLF2 and KLF4. This atheroprotective endothelial phenotype, together with a decrease in LP retention, promotes an antiinflammatory and antithrombotic environment that affords relative protection from atherosclerotic lesion development.

Question 18

define epigeneticcs

Answer 18

EPIGENETICS: functionally relevant, inheritable changes to the genomethat do not involve a change in thenucleotide sequence, which affect gene expression

Question 19

3 epigenetics mechanisms

Answer 19

DNA methylation
Histones modifications
miRNA

Question 20

blood flow regulates endothelial epigenetic pathways - STABLE FLOW

Answer 20

A: Stable flow (s-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.

Question 21

blood flow regulates endothelial epigenetic pathways - DISTURBED FLOW

Answer 21

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

Question 22

define angiogenesis

Answer 22

Angiogenesis is the sprouting of new vessels from the endothelial lining of preexisting vessels.

Question 23

what is angiogenesis essential for

Answer 23

embryonic development
menstrual cycle
wound healing

Question 24

how does angiogenesis take place

Answer 24

Angiogenesis is totally controlled by endothelial cells and has a role in atherosclerosis

This process is more relevant to disease - e.g. it is crucial in cancer

When tissue is hypoxic, it will release chemicals which activates the existing blood vessels which triggers a change in the cells

The cells that becomes a tip cell takes over and controls the formation of the blood vessel

You end up with a stabilised blood vessel forming

Question 25

the janus paradox of angiogenesis and cardiovascular disease

Answer 25

• angiogenesos promotes plaque growth

- therapeutic angiogenesis prevents damage post-ischemia

Question 26

define cellular senescence:

Answer 26

: growth arrest that halts the proliferation of ageing and/or damaged cells.

Senescence is a response to stress and damage.
Senescent cells have distinctive morphology and acquire specific markers (e.g. b-gal)

Question 27

the good and the bad of senescence

Answer 27

Good
Prevents the transmission of damage to daughter cells.
Replicative senescence: the limited proliferative capacity of human cells in culture.

Not so good
Senescent cells are pro-inflammatory and contribute to many diseases.

Question 28

senescent endothelial cells are found in

Answer 28

atherosclerotic lesions

Question 29

Endothelial cell senescence can be induced by

Answer 29

Endothelial cell senescence can be induced by cardiovascular risk factors eg oxidative stress

Question 30

what phenotypes do senescent cells have?

Answer 30

Senescent cells have a proinflammatory and prothrombotic phenotype and therefore may contribute to atherosclerosis plaque progression and its complications

Question 31

overview of atherosclerosis

Answer 31

At the beginning you have risk factors which activate the endothelium and promotes permeability, leukocyte adhesion and leukocyte migration

Leukocytes which enter the subendothelial layer begin to phagocytose LDLs and form foam cells producing fatty streaks

After a long time, this becomes a large complex plaque with angiogenesis and senescence possible playing a role

Question 32

why can red wine be beneficial

Answer 32

NOTE: Red wine contains RESVERATROL which has anti-inflammatory properties on the endothelium

Red wine has a hormetic action - it is beneficial at lower doses and has cytotoxic effects at higher doses

Question 33

Endothelial atheroprotective genes and vascular homeostasis

Answer 33

Endothelial atheroprotective genes and vascular homeostasis. The expression of atheroprotective genes in vascular endothelium is regulated by key transcriptional factors (eg, Kruppel-like factor [KLF]-2, KLF4, and nuclear factor erythroid 2-related factor [Nrf]-2) in response to hemodynamic, hormonal, and environmental stimuli. The coordination of this genetic program is further influenced by micro-RNAs (miRNAs), epigenetic modifications, and pharmacological agents. The resultant vasoprotective endothelial phenotype supports a spectrum of functions critical to the maintenance of vascular homeostasis.