Blood vessel order, function & specialisation of cells

Question 1

Name the 3 layers of blood vessels

Answer 1

Tunica adventitia

Tunica media

Tunica intima

Question 2

Name the 3 layers which make up blood vessels. State what they are made out of and their function?

Answer 2

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 3

What is a vascular endothelium?

Answer 3

Vascular endothelium – single cell layer that acts as the blood-vessel interface

Question 4

List 5 functions of the vascular endothelium and explain what each one means?

Answer 4

Vascular endothelial functions:

Vascular tone management – secretes and metabolises vasoactive substances – this can cause vasoconstriction or vasodilation (kind of like a local paracrine gland)

Thrombostasis – secretes anti-coagulant substances

Absorption + Secretion- allow active/passive transport via diffusions/channels

Barrier – prevents entry of bad substances hence preventing atherosclerosis formation

Growth – mediates cell proliferation

Question 5

Blood vessel can regulate its own pressure depending on how much blood is flowing past it (SHEAR STRESS)

There are mechanoreceptors in the endothelial cells which detects an increased blood flow which then secretes vasodilators to bring the blood flow down

Answer 5

Question 6

List 2 vasodilators and 3 vasoconstrictors

Answer 6

VASODILATORS

Nitric Oxide- Inhibits aggregation of platelets

PGI2 (prostacyclin) -Cardioprotective molecule, Inhibits aggregation of platelets

VASOCONSTRICTORS

TXA2 (thromboxane) -Produced in endothelial cells but also by platelets , activate other platelets which stimulates aggregation

ET-1 (endothelin 1)

Angiotensin II (ANG II)

Question 7

Summary table for key mediators

Answer 7

Question 8

List the functions of the following molecules

Nitric Oxide

PG12- prostacyclin

TXA2-Thromboxane

Answer 8

VASODILATORS

Nitric Oxide -Inhibits aggregation of platelets

PGI2 (prostacyclin)- Cardioprotective molecule, Inhibits aggregation of platelets

VASOCONSTRICTORS

TXA2 (thromboxane)

Produced in endothelial cells but also by platelets

Activate other platelets which stimulates aggregation

Question 9

Vascular Tone is controlled by the balance of the forces causing vasoconstriction and vasodilation

Answer 9

Question 10

Answer 10

Question 11

Draw a diagram showing how a phospholipid components can be changed into Thromboxane A2, Prostacyclin and PGD2, PGE2 and PGF2 and leukotrines

Answer 11

A phosphlipid can be converted to arachidonic acid by Phospholipase A2

The arachidonic acid can then be converted to Prostaglandin H2 (PGH2) by the COX enzymes (COX = cyclooxygenase)

COX 1 is expressed in ALL CELLS

If your body has an inflammatory problem, COX2 will be upregulated so typically COX2 is associated with inflammation, and hence, disease

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

Thromboxane is a powerful VASOCONSTRICTOR and it stimulates platelet aggregation

Some of the other products that PGH2 can be converted to are involved in the health of the epithelia in the GI tract

Question 12

What enzyme converts phospholipid into arachidonic acid?

Answer 12

phosphlipid can be converted to arachidonic acid by Phospholipase A2

Question 13

What enzyme converts Arachinidonic acid into prostaglandin H2 (PGH2)?

Answer 13

The arachidonic acid can then be converted to Prostaglandin H2 (PGH2) by the COX enzymes (COX = cyclooxygenase)

COX 1 is expressed in ALL CELLS

If your body has an inflammatory problem, COX2 will be upregulated so typically COX2 is associated with inflammation, and hence, disease

Question 14

What enzyme converts PGH2 into Thromboxane A2 and Prostacyclin?

Answer 14

Thrombocane Synthase

Prostacyclin Synthase

Question 15

List 3 effects of Thromboxane A2 and Prostacyclin

Answer 15

THEY HAVE OPPOSITE EFFECTS​

Question 16

How is NO produced and how does this lead to relaxation of smooth muscle?

Answer 16

ACH-Something that stimulates NO production will bind to the G-protein coupled receptor and activate Phospholipase C

PLC converts PIP2 to IP3 and DAG

IP3 moves to the endoplasmic reticulum and stimulates CALCIUM EFFLUX

The rise in intracellular calcium concentration upregulates endothelial nitric oxide synthase (eNOS)

eNOS catalyses the following conversion:

L-arginine + Oxygen —–> L-citrulline + NO

NO exits the endothelial cell and moves the smooth muscle cell

NO moves in to the smooth muscle and upregulates the activity of Guanylyl Cyclase which converts GTP to cGMP

cGMP upregulates Protein Kinase G which eventually leads to relaxation of smooth muscle (calcium efflux reduces tension within the myocyte and stimulates relaxation)

SHEAR stress (force of blood going across the endothelial cells) is also a stimulator - it can upregulate endothelial NO

Question 17

REMEMBER THE SUMMARY SLIDE

Answer 17

Question 18

List the steps for how prostacyclin is produced and how it causes vessel dilation?

Answer 18

Produced inside endothelial cells

Binds to the IP receptor which is coupled with adenylate cyclase which converts ATP to cAMP

cAMP upregulates Protein Kinase A which results in RELAXATION of the vascular smooth muscle causing vasodilation

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

Question 19

Recall the steps which causes Thrombocane A2 to cause vasoconstriction?

How does thromboxane A2 cause a positive feedback effect

Answer 19

Thromboxane

Can bind to the following receptors:

Alpha - PLATELETS

Beta - VASCULAR SMOOTH MUSCLE CELLS

Beta Receptor = coupled with phospholipase C which converts PIP2 to IP3 which results in the constriction of blood vessels

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 20

Draw a diagram showing how Angiotensin II is produced ?

State 5 effects of angiotensin 2

Answer 20

Question 21

List the steps for how angiotensin 2 causes vessel constriction?

Answer 21

Angiotensin II will bind to an angiotensin receptor on vascular smooth muscle cells which leads to the activation of PLC and hence the conversion of PIP2 to IP3 resulting in CONTRACTION

NOTE: this is because IP3 production causes an increase in the transport of calcium (massive 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)

These are both mechanisms to INCREASE BLOOD PRESSURE

REMEMBER: ACE ALSO BREAKS DOWN BRADYKININ

Bradykinin has the OPPOSITE EFFECT to angiotensin II

So breaking down bradykinin is important to cause vasoconstriction

Bradykinin itself can stimulate 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

Question 22

List the steps for how Endothelin-I causes vessel constriction and dilation?

Take note of the agonists and the antagonists

Answer 22

We start off inside 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

Endothelin-1 is then pushed out of the endothelial cell and it can bind to alpha or beta receptors

BOTH alpha AND beta receptors ON SMOOTH MUSCLE are bound to PLC which converts PIP2 to IP3 which causes CONTRACTION

If the endothelin-1 binds to a beta receptor ON THE ENDOTHELIAL CELL - it triggers the activation of eNOS

eNOS converts L-arginine and oxygen to L-citrulline and Nitric Oxide

The Nitric Oxide then moves into the smooth muscle cells and stimulates RELAXATION

Antagonists which inhibit the production of the endothelin-1 precursor:

Prostacyclin

Nitric Oxide

ANP (atrial natriuretic peptide)

Heparin

HGF (hepatocyte growth factor)

EGF (epidermal growth factor)

Agonists which stimulate the production of endothelin-1:

Adrenaline

Vasopressin

Angiotensin II

Interleukin-1

Question 23

How is Aspirin beneficial to the cardiovascular system- what is its mechanism of action?

What effect does low-dose aspirin have?

Answer 23

Aspirin causes irreversible inhibition of the COX enzymes

NOTE: NSAIDs cause reversible inhibition of the COX enzymes

Aspirin has different effects on COX1 and COX2

COX1 - inactivation

COX2 - switches its function (to generating protective lipids)

If you reduce the conversion of arachidonic acid to PGH2 then you reduce the amounts of prostacyclin and thromboxane

When thinking of thromboxane, this effect is good but aspirin also decreases the production of prostacyclin

However, with low-dose aspirin, Prostacyclin levels will decrease slightly and then remain relatively high whereas thromboxane levels continue to fall

This is because thromboxane is predominantly produced in the platelets (also in the endothelial cells but mainly 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

So if we continue to take low-dose aspirin, we get a decrease in thromboxane but maintenance of prostacyclin

Question 24

Aspirin has different effects on COX1 and COX2

What are these effects

Answer 24

Aspirin has different effects on COX1 and COX2

COX1 - inactivation

COX2 - switches its function (to generating protective lipids)

Question 25

What effect does low dose aspirin have on thromboxane and prostacyclin and why?

Answer 25

Aspirin has different effects on COX1 and COX2

COX1 - inactivation

COX2 - switches its function (to generating protective lipids)

If you reduce the conversion of arachidonic acid to PGH2 then you reduce the amounts of prostacyclin and thromboxane

When thinking of thromboxane, this effect is good but aspirin also decreases the production of prostacyclin

However, with low-dose aspirin, Prostacyclin levels will decrease slightly and then remain relatively high whereas thromboxane levels continue to fall

This is because thromboxane is predominantly produced in the platelets (also in the endothelial cells but mainly 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

So if we continue to take low-dose aspirin, we get a decrease in thromboxane but maintenance of prostacyclin

Question 26

Why does low-dose aspirin block the synthesis of Thromboxane-A2 and not Prostacyclin?

Choose from below

Platelets are ‘stickier’ than endothelial cells

Platelets are anucleated

Platelets have a short life-span

Platelets circulate the body

Answer 26

Platelets are anucleated

Although all these answers are ’true’, the question focusses on linking ‘cause’ and ‘effect’. Although platelets form a platelet plug, are sticky (when activated, especially compared with the slick luminal surface of , have a short lifespan and circulate the body, the reason TXA2 synthesis is impacted more by aspirin than PGI2 synthesis is that platelets are the major source of TXA2 (thromboxane synthase is predominantly expressed in platelets, whereas prostacylin synthase is predominant in endothelial cells). Platelets have no nucleus to replace the COX enzymes that aspirin permanently disables. New production relies on the production of new platelets. Conversely, endothelial cells can generate new enzymes from their nucleus.

Question 27

Which of the following statements are incorrect?

Renin converts angiotensinogen to angiontensin I

Ca2+ concentration is higher inside versus outside the cell

Phosphodiesterase inhibitors promote vasodilation

Aspirin anticoagulates the blood

Answer 27

Ca2+ concentration is higher inside versus outside the cell

Renin definitely converts angiotensinogen to angiotensin I, and angiotensin converting enzyme subsequently converts angiotensin I to angiotensin II.

Although there are rich intracellular calcium stores (e.g. smooth ER), the cytosol, which is very very low in calcium, certainly compared with the extracellular space

Phosphodiesterase enzymes break down cGMP, reducing the vasodilatory effect. Therefore, inhibition of these enzymes potentiates the vasodilatory effect.

Aspirin is an antiplatelet medication. It is not involved in the coagulation cascades that result in formation of a clot.

Question 28

Does increased inositol triphosphate (IP3) always leads to vasodilation?

Yes, calcium exposes actin active sites

Yes, calcium changes membrane potential

No, it varies between cells

No, IP3 only leads to vasoconstriction

Answer 28

No, it varies between cells

Inositol triphosphate itself does not ‘cause’ vasodilation. Instead, it is a key component of the calcium second messenger system. The question does not refer to vascular smooth muscle cells specifically (otherwise option 4 would be the correct answer!). Think about the endothelial cell. An influx in calcium upregulates eNOS, which leads to increased nitric oxide production. NO diffuses out of the endothelial cell and into the vascular smooth muscle cells (VSMCs) to stimulate vasodilation. IP3 in VSMCs increases cytosolic calcium and invariably causes contraction and hence, vasoconstriction.

Question 29

Regarding functions of angiotensin II, which of the following is not true?

It increases aldosterone secretion

It reduces heart rate

It reduces urine output

It binds to receptors in the brain

Answer 29

It reduces heart rate

Angiotensin II has five main effects, one of which is increased aldosterone secretion from the adrenal gland.

Angiotensin II increases sympathetic nerve activity, which increases the rate of sinoatrial depolarisation, leading to an increase in heart rate.

Urine output is greatly reduced via many mechanisms, vasoconstriction of renal vessels, ADH-driven water reabsorption from the collecting ducts, and Aldosterone-driven sodium (and water) reabsorption.

Angiotensin II binds to receptors in the brain to release antidiuretic hormone from the pituitary gland.