8. Vascular endothelium 1

Question 1

Main functions of components cardiovascular system

Answer 1

Heart: muscular pump to generate flow
Arteries: thick muscular walls, stabilise pulsatile flow
Capillaries: very thin walls, facilitate gas and solute exchange
Veins: one-way valves, maintain unidirectional flow

Question 2

5 Key functions of vascular endothelium

Answer 2

Managing Vascular tone: Secretes and metabolises vasoactive substances
Thrombostasis: Prevents clots forming or molecules adhering to vessel wall
Absorption and Secretion: Allows active/passive transport via diffusion/channels
Barrier: Prevents atheroma development and impedes pathogens (selective)
Growth: Mediates cell proliferation and where blood vessels are

Question 3

Which 3 key mediators cause contraction?

Answer 3

Thromboxane A2
Endothelin-1
Angiotensin II

Question 4

Which 3 key mediators cause relaxation?

Answer 4

Nitric oxide
Prostacyclin
Endothelin-1

Question 5

Normotensive

Answer 5

Widening and shrinking forces in equilibrium

may oscillate in 1 direction slightly when necessary

Question 6

Hypertensive (and how is this managed?)

Answer 6

Vasoconstricting factors “putting in more effort than they should”
-Drugs can modify factors to restore equilibrium and lower BP

Question 7

How can vascular endothelial function be assessed?

Answer 7

Laser Doppler flowmetry

Flow-mediated dilation

Question 8

Arachidonic acid:
Synthesised from?
Converted to? and by what?
What happens to this?

Answer 8

Synthesised from: Phospholipids
Converted to prostaglandin precursor by COX enzymes
Further converted to different molecules depending on what enzymes it is exposed to

Question 9

What can the prostaglandin precursor (PGH2, from arachidonic acid) be converted to? What do these do?

Answer 9

Prostacyclin: vasodilator, anti-atherogenic, anti-platelet
Thromboxane A2: vasoconstrictor, pro-atherogenic, pro-platelet
PGD2, PGE2,PGF2: Prostaglandins, cause pain, fever, inflammation

Question 10

What irreversibly disables COX enzymes? Why would this be used therapeutically? What is the consequence?

Answer 10

Aspirin
Useful for those at risk of clotting, pain and inflammation
Comes at cost of disabling prostacyclin

Question 11

What is the abbreviation for vascular smooth muscle cells?

Answer 11

VSMC

Question 12

Summarise NO in VSMC

Answer 12

NO produced by endothelial cell
Results in relaxation of VSMC
Shear stress can influence how NO is produced

Question 13

Describe the effects of Prostacyclin on VSMC

Answer 13

Prostacyclin binds to a membrane receptor
Receptor linked to membrane bound enzyme (GPCR)
Adenyl cyclase converts ATP to cAMP
cAMP inhibits MLCK
Reduced cross bridge cycling
Cell relaxes
Vasodilation

Question 14

Which 2 places does Thromboxane A2 go?

Answer 14

Towards VSMCs

Out into bloodstream

Question 15

Describe Thromboxane A2’s effect on VSMC

Answer 15

Binds to thromboxane receptor linked to phospholipase C (PLC)
PLC converts PIP2 to IP3
IP3 triggers Ca2+ influx from extracellular space and SER
Ca2+ upregulates MLCK
Vasoconstriction

Question 16

Describe Thromboxane A2’s effect on platelets

Answer 16

Binds to receptors on platelets
Causes them to change into a more active shape (+ produces more TXA2: positive feedback)
Increases their ability to aggregate and stick to endothelium
= useful when endothelium is damaged

Question 17

Where is Angiotensinogen produced? What form is it?

Answer 17

Liver

Inactive

Question 18

Where is renin produced and what happens to angiotensinogen in the presence of renin?

Answer 18

Renin produced by kidney

Angiotensinogen cleaved to form Angiotensin I

Question 19

Where is ACE expressed and what does it do to angiotensin I?

Answer 19

ACE is expressed in endothelial cells of vessels in lungs and kidneys
Angiotensin I is converted to Angiotensin II (active form)

Question 20

What are the 5 effects of angiotensin II?

Answer 20

Increase ADH secretion from pituitary: Leads to vasoconstriction and increased H2O retention
Increase Aldosterone secretion: Increases Na+ reabsorption, increases H2O retention
Direct interaction with nephron to increase Na+ reabsorption, increases H2O retention
Increase sympathetic excitation: Increases Cardiac Output, vasoconstriction and pressure
Direct interaction with endothelial cells to cause increased arteriolar vasoconstriction: Increases BP

Question 21

Simplify the effects of angiotensin II

Answer 21

Increases BP by increasing water reabsorption and vasoconstriction

Question 22

Describe the mechanism of activation/ action of angiotensin II

Answer 22

Renin cleaves angiotensinogen to Ang I
Ang I cleaved to form Ang II by ACE
Ang II diffuses across endothelium and binds to AT1 receptor
PLC migrates along membrane and converts PIP2 to IP3
IP3 triggers Ca2+ influx
Ca2+ upregulates MLCK
Cell contracts
ACE metabolises bradykinin (which causes vasodilation)
NO-mediated vasodilation is reduced
Vessel constricts

Question 23

What are the actions of Endothelin-I? What is its main effect?

Answer 23

Simultaneously causes vasoconstriction and vasodilation

Main effect: Vasoconstriction

Question 24

Where is Endothelin-I produced?

Answer 24

In nucleus of endothelial cells

As a precursor (zymogen): Big Endothelin-I

Question 25

Describe the mechanism causing vasoconstriction of Endothelin-I

Answer 25

Endothelin converting enzyme converts zymogen to ET-1
ET-1 binds to ETA and ETB receptors on VSMC
Receptors release PLC
PLC converts PIP2 to IP3
IP3 triggers Ca2+ influx
Cell contracts
Vessel constricts

Question 26

Describe the mechanism causing vasodilation of Endothelin-I

Answer 26

Endothelin converting enzyme converts zymogen to ET-1
ET-1 binds to ETB on endothelial cell
Upregulates eNOS
Increased NO production
NO diffuses into VSMC
Cell relaxes
Vessel dilates

Question 27

What would be a good mode of action in a drug for hypertension?

Answer 27

Calcium channel blockers
Block flow of calcium into VSMCs
Impede cross-bridge cycling

Question 28

COX-1

Answer 28

Constitutively expressed (all cells)
Aspirin acetylation inactivates

Question 29

COX-2

Answer 29

Upregulated in times of physiological insult

Aspirin acetylation switches its function to generating protective lipids

Question 30

What is the general effect of aspirin on COX enzymes?

Answer 30

Aspirin causes irreversible inhibition

Subsequently stopping prostaglandin/ thromboxane synthesis

Question 31

What cause reversible inhibition of COX enzymes?

Answer 31

Other NSAIDs

COX-2 specific inhibitors

Question 32

What do Nitrovasodilators do?

Answer 32

Donate exogenous NO

Cause vasodilation