Cardiovascular Systems 8 - Vascular Endothelium

Question 1

Define vascular endothelium

Answer 1

One cell thick layer of cells that act as the blood-vessel interface

Question 2

List the main fuctions of the vascular endothelium

Answer 2

• Determines vascular tone via secretion of vasoactive compounds
• Thrombostasis prevents clots forming or molecules adhering to cell walls
• Allows absorption and secretion
• Mediates cell proliferation

Question 3

When is thromboxane A2 likely to be expressed?

Answer 3

• In times of haemostatic crisis

- If a platelet plug is needed to be generated due to a small bleed

Question 4

Describe the stages of the synthesis process undergone to make Thromboxane A2 and prostacyclin.

Answer 4

• First, phospholipids from the cell membrane are converted to arachidonic acid via phospholipase A2
• Arachidonic acid is converted to prostagladin H2 by COX1 and COX2 (COX1 is expressed in all cells, COX2 only in times of stress)
• Thromboxane A2 is produced by thromboxane synthase
• Prostacyclin is produced by prostacyclin synthase

Question 5

What else, other than thromboxane and prostacyclin, can prostagladin H2 be converted to?

Answer 5

PGD2, PGE2, PGF2

Question 6

List the main effects of thromboxane A2

Answer 6

• Vasoconstrictor
• Pro-atherogenic
• Pro-platelet

Question 7

List the main effects of prostacyclin

Answer 7

• Vasodilatory
• Anti-atherogenic
• Anti-platelet

Question 8

List the sequence of events that occur following the binding of acetylcholine to smooth muscle

Answer 8

• Acetylcholine binds to a GPCR, resulting in PLC converting PIP2 to IP3
• IP3 triggers Ca2+ influx from the ER
• Ca2+ activations endothelial NO synthase
• Endothelial NO synthase catalyses the conversion L-Arg + oxygen to L-Cit + nitric oxide
• DAG is involved in the production of arachidonic acid, producing thromboxane or prostacyclin

Question 9

Describe the effects of NO following its production in the vascular endothelium.

Answer 9

• NO travels to smooth muscle, converting GTP to cGMP
• This upregulates PKG, which activated potassium channels.
• The membrane hyperpolarises, so the cell relaxes and vasodilation occurs

Question 10

Describe the effects of prostacyclin following its production in the vascular endothelium, summarising the metabolic pathway

Answer 10

• Prostacyclin travels to the smooth muscle and binds to IP receptors, causing upregulation of adenyl cyclase
• Adenyl cyclase converts ATP to cAMP, which inhibits myosin light chain kinase
• This reduces cross bridge formation, and the vessel dilates.

Question 11

Describe the effects of thromboxane A2 following its production in the vascular endothelium, summarising the metabolic pathway causing changes in the diameter of the blood vessel

Answer 11

• Thromboxane binds to TPb receptors on the vascular scmooth muscle membrane
• PLC as a result converts PIP2 to IP3
• IP3 triggers Ca2+ influx, upregulating myosin light chain kinase and causing vessel contraction.

Question 12

Describe the effects of thromboxane A2 on platelet aggregation, listing the metabolic pathway

Answer 12

Thromboxane also binds to TPa receptors on the platelets, stimulating the platelet to make more thromboxane, resulting in platelet aggregation

Question 13

Describe the stages that occur in the production of angiotensin 2

Answer 13

• Angiotensinogen is produced at the liver
• Renin from the kidney stimulates production of angiotensin I
• Angiotensin converting enzyme (from the lungs and kindney) catalyses the conversion of angiotensin I to angiotensin II

Question 14

List the main actions of angiotensin 2

Answer 14

• ADH secretion, causing increased water retention
• Aldosterone secretion (increases water retention)
• Increased sodium reabsorption (and water follows)
• Sympathoexcitation (excites the SNS, resuliting in increased vascular resistance)

Question 15

Describe the metabolic pathway following angiotensin 2 binding to angiotensin 1 receptors.

Answer 15

• PLC is produced
• It converts PIP2 to IP3
• Causes calcium influx and therefore contraction
• Angiotensin converting enzyme alosmetabolises bradykinin
• This reduces NO mediated vasodilation
• Vessel constricts

Question 16

Describe the metabolic pathway in the cell due to endothelin 1

Answer 16

• The endothelial cell nucleus produces big endothelin 1
• Endothelin converting enzyme converts zymogen to ET-1
• ET-1 binds to ET(A) and ET(B) receptors on vascular smooth muscle cells
• Receptors release PLC
• IP3 is made, and this triggers CA2+ influx.
• The vessel constricts (main action)
• ET-1 also binds to ETa, upregulating eNOS, and producing NO (causing some vessel dilation)

Question 17

Describe the mechanism of aspirin.

Answer 17

• Aspirin acetylation inactivates cox-1, while it switches the function of cox-2 to generate protective lipids.
• Aspirin causes irreversible inhibition, reducing synthesis of thromboxane and prostacyclin
• This means that levels of thromboxane decrease, and levels of prostacyclin remain the same.
• This is because thromboxane is expressed in platelets, while prostacyclin is produced in the endothelial cells, which have nuclei so constantly produce enzyme. When the synthesis of thromboxane is inhibited, the platelets cant produce any new enzymes as they have no nucleus.

Question 18

Describe the risks of drug use, such as aspirin

Answer 18

• The drug affects many different tissues, it is not always tissue specific
• The expression of receptors varies between tissues
• Different people experience different side effects

Question 19

How can calcium channel blockers be useful in treatment of hypertension?

Answer 19

They prevent calcium entering the vascular smooth muscle cells, so that the muscle cannot contract and dilation occurs

Question 20

How are nitrovasodilators useful in treatment of hypertension?

Answer 20

They donate exogenous NO, which acts as a vasodilator