Blood vessel order, function and cell specialisation

Question 1

What are the three layers of blood vessels?

Answer 1

Tunica adventitia
• External layer containing blood vessels, fibrous tissue, elastin, collagen
• Helps keep the shape of the blood vessel

Tunica media
• Predominantly smooth muscle cells able to contract or dilate depending on the type of stimulus

Tunica intima
• Predominantly vascular endothelium has the elastic basal lamina as well – this is the exchange surface

Question 2

What are the function of endothelium?

Answer 2

• Vascular tone management – secretes and metabolises vasoactive substances – this can cause vasoconstriction or vasodilation (balance)
• Thrombostasis – secretes anti-coagulant substances (prevents clots or molecules sticking to the vessel)
• Absorption + Secretion – allows diffusion etc.
• Barrier – prevents entry of bad substances, preventing atherosclerosis formation
• Growth – mediates cell proliferation

Question 3

What do mechanoreceptors in endothelial cells do?

Answer 3

Detects increased blood flow – secretion of vasodilators

Question 4

Name 2 types of vasodilators

Answer 4

Nitric Oxide – inhibits platelet aggregation

PGI2 (Prostacyclin) – inhibits platelet aggregation and cardioprotective molecule

Question 5

Name 3 types of vasoconstrictors

Answer 5

TXA2 (Thromboxane) – made by endothelial cells and platelets – activates other platelets

ET – 1 (endothelin 1) – can cause constriction and dilation due to different receptors on diff tissues

Angiotensin II

Question 6

What is an example of a stressor that upregulates NO production?

Answer 6

Shear stress force of blood going across the endothelial cells

Question 7

How does Nitric Oxide work?

Answer 7

• NO production stimulator binds to G-protein coupled receptor
• Activation of Phospholipase C
• PLC converts PIP2 to IP3 and DAG
• IP3 moves to ER and stimulates calcium efflux
• Leads to upregulation of endothelial nitric oxide synthase (eNOS)
• eNOS catalyses the following conversion: L-arginine + Oxygen —–> L-citrulline + NO
• NO exits the endothelial cell and moves to the smooth muscle cell
• Here it upregulates the activity of Guanylyl Cyclase which converts GTP to cGMP
• cGMP upregulates Protein Kinase G which leads to relaxation of smooth muscle (calcium efflux reduces tension within the myocyte and stimulates relaxation)

Question 8

How does ACh cause vasodilation?

Answer 8

It triggers the upregulation of endothelial nitric oxide - you get steady vasodilation

Question 9

If the endothelium is destroyed which drug can be given to cause vessel dilation?

Answer 9

SNP – a nitric oxide donor

Question 10

What is arachidonic acid made from and by what?

Answer 10

Phospholipid can be converted to arachidonic acid by Phospholipase A2

Question 11

What two things can be made from arachidonic acid?

Answer 11

• Arachidonic acid can be converted to PGH2 by the COX enzymes (COX = cyclooxygenase)
• PGH2 is a precursor which can be exposed to a variety of enzymes to produce different products
• PGH2 can either becomes:
Prostacyclin (PGI2)
By Prostacyclin Synthase

  Thromboxane A2 (TXA2)
  By Thromboxane Synthase

Question 12

What is the role of thromboxane?

Answer 12

• It is a powerful vasoconstrictor and it stimulates platelet aggregation
• It enables the formation of atheromatous plaques

Question 13

Which receptors does thromboxane bind to?

Answer 13

• Alpha - platelets

* Beta - vascular smooth muscle cells

Question 14

How does thromboxane lead to vasoconstriction?

Answer 14

• Binds to the beta receptor which is coupled with phospholipase C
• Converts PIP2 to IP3 which results in the constriction of blood vessels

Question 15

How does thromboxane lead to platelet aggregation?

Answer 15

When thromboxane binds to the alpha receptors on platelets it results in the activation of platelets and the production of more thromboxane which has a domino effect on other platelets and stimulates aggregation

Question 16

What is the role of prostacyclin?

Answer 16

• Causes vasodilation
• Inhibits the formation of atheromatous plaques
• Stops platelet aggregation

Question 17

Where is COX 1 expressed?

Answer 17

in all cells

Question 18

What happens to COX 2 during inflammation?

Answer 18

It will be upregulated

Question 19

What happens when arachidonic acid follows the leukotriene pathway?

Answer 19

• If arachidonic acid follows the lipoxygenase enzyme cascade you end up with LTD4 and others
• LTD4 causes bronchoconstriction - associated with asthma
• Montelukast therapy can reduce bronchoconstriction helping the patient breathe more comfortably

Question 20

Where else can arachidonic acid be produced from?

Answer 20

From DAG via DAG lipase

Question 21

What happens if arachidonic acid is exposed to lipoxygenase?

Answer 21

Goes down the leukotriene route

Question 22

What happens if arachidonic acid is exposed to COX?

Answer 22

It goes down the prostaglandin route

Question 23

How does prostacyclin lead to vasodilation?

Answer 23

• Produced inside endothelial cells
• Binds to the IP receptor
• Adenylate cyclase activated which converts ATP to cAMP
• cAMP upregulates Protein Kinase A
• Results in relaxation of the vascular smooth muscle causing vasodilation

Question 24

Where else is prostacyclin released and what are its effects?

Answer 24

Prostacyclin is also secreted into the blood where it has anti-platelet aggregation properties

Question 25

Where is endothelin – 1 produced?

Answer 25

In the nucleus, an endothelin precursor is produced which is then cleaved by Endothelin Converting Enzyme (which is embedded in the membrane) to produce endothelin-1

Question 26

Where does endothelin -1 bind on smooth muscle?

Answer 26

* Alpha and beta receptors on smooth muscle | * They are bound to PLC which converts PIP2 to IP3 which causes contraction

Question 27

What happens if endothelin- 1 binds to beta receptors on an endothelial cell?

Answer 27

* It triggers the activation of eNOS * eNOS converts L-arginine and oxygen to L-citrulline and Nitric Oxide * Nitric Oxide then moves into the smooth muscle cells and stimulates relaxation

Question 28

Name antagonists which inhibit the production of the endothelin-1 precursor

Answer 28

* Prostacyclin * Nitric Oxide * ANP (atrial natriuretic peptide) * Heparin * HGF (hepatocyte growth factor) * EGF (epidermal growth factor)

Question 29

Name agonists which stimulate the production of the endothelin-1 precursor

Answer 29

* Adrenaline * Vasopressin * Angiotensin II * Interleukin-1

Question 30

How does angiotensin lead to vasoconstriction?

Answer 30

* Angiotensin II will bind to an angiotensin receptor on vascular smooth muscle cells * Leads to activation of PLC and conversion of PIP2 to IP3 resulting in contraction * This is because IP3 causes calcium influx which will increase the amount of cross-bridge cycling that takes place * Some AT receptors are G-protein coupled but are instead bound to SRC which can upregulate the growth of vascular smooth muscle cells (this may also have some effect on contractility)

Question 31

What is bradykinin and how does ACE affect it?

Answer 31

* It stimulates vasodilation * Bradykinin can bind to the bradykinin receptor-1 and activate PLC which converts PIP2 to IP3 which upregulates the production of Nitric Oxide (due to a rise in intracellular calcium) * Nitric Oxide then moves to the smooth muscle and causes relaxation * Ace breaks down bradykinin so that angiotensin 2 has its desired effect

Question 32

To increase blood vessel diameter, what must be increased and how?

Answer 32

• Amount of nitric oxide • This can be done by: - Stimulating the production of nitric oxide (endothelium dependent) - Donating nitric oxide (endothelium independent)

Question 33

Why would you donate NO to a person with microvascular disease to increase the vessel diameter and decrease blood flow?

Answer 33

Donation of nitric oxide is endothelium-independent

Question 34

Besides stimulating NO production or donating NO, how can we influence NO?

Answer 34

* Enhancing the effects of the nitric oxide that's already there * Stop the degradation of nitric oxide or stop the degradation of some of the steps to make nitric oxide

Question 35

What is the mechanism for Nitric Oxide Donors?

Answer 35

* Both endogenous and exogenous NO will activate Guanylyl Cyclase which converts GTP to cGMP * The cGMP then activates Protein Kinase G which causes relaxation

Question 36

How does Viagra work?

Answer 36

* cGMP is converted to GMP by Phosphodiesterase * GMP is metabolically inactive (cGMP normally would activate PKG which causes contraction) * Viagra is a phosphodiesterase inhibitor

Question 37

What affect does aspirin have on COX enzymes?

Answer 37

* Aspirin causes irreversible inhibition of the COX enzymes | * (NSAIDs cause reversible inhibition of the COX enzymes)

Question 38

What effect does aspirin have on COX1 and COX2?

Answer 38

COX1 – inactivation COX2 - switches its function

Question 39

Why does reducing arachidonic acid conversion to PGH2 (aspirin) have good and bad effects?

Answer 39

There is a reduce in the amounts of thromboxane (bad) There is a decrease the production of prostacyclin

Question 40

Why does low dose aspirin cause prostacyclin level to level off but thromboxane to continue to decrease?

Answer 40

* Thromboxane is predominantly produced in the platelets | * Platelets do not have a nucleus, so they can't generate more mRNA to produce new proteins to build the enzyme again

Question 41

Why do we have to be careful when blocking calcium channels?

Answer 41

they are found in the heart

Question 42

How does smooth muscle cell and cardiomyocyte RMP differ? Why is this useful when it comes to calcium channel blockers?

Answer 42

* Smooth muscle cells have a higher membrane potential (more positive) than cardiomyocytes * The affinity of the channel blocker to the channel is related to the membrane potential of target cells

Question 43

How can ACE inhibitors be used to cause vasodilation?

Answer 43

* Inhibits the breakdown of bradykinin | * By decreasing the breakdown of bradykinin, it stimulates relaxation because bradykinin has a vasodilatory effect

Question 44

Why does a damaged endothelium lead to a platelet plug?

Answer 44

* If the endothelium is damaged, it exposes parts of the sub-endothelial layer (usually collagen) which is sticky causing platelets to adhere to it * Platelets stick and release thromboxane which stimulates the aggregation of platelets

Question 45

Which drugs involve Gq protein linked receptor (PLC, PIP2, IP3, DAG)?

Answer 45

* Nitric Oxide production * Thromboxane action * Endothelin 1 action * Angiotensin II action

Question 46

Which drugs involve guanylate cyclase (GTP, cGMP, Protein Kinase G)?

Answer 46

Nitric Oxide action

Question 47

Which drugs involve adenylate cyclase (ATP, cAMP, Protein Kinase A)?

Answer 47

Prostacyclin action