Blood vessel order, function & specialisation of cells in the cardiovascular system Flashcards
What are the three layers of blood vessels?
Tunica intima -
Contains elastic basal lamina
in contact with the endothelium: this is the exchnage surface
Tunica media - mainly smooth muscle which is able to contract or dilate depending on the type of stimulus
Tunica adventitia - external layer containing blood vessels, collagen, elastin and fibrous tissue. This helps keep the shape of the blood vessel.
What is the vascular endothelium and what are the functions of the vascular endothelium?
Single cell layer of cells that acts as the blood-vessel interface.
1.Barrier
Prevents atheroma development & impedes pathogens
2.Growth
Mediates cell proliferation
3.Absorption + Secretion
Allows active/passive transport via diffusion/channels
4.
Thrombostasis
Prevents clots forming or molecules adhering to vessel wall
5.Vascular tone management
Secretes and metabolises vasoactive substances
How do blood vessels regulate its own blood pressure?
Blood vessels regulate their own pressure depending on how much blood is flowing past it (SHEAR STRESS).
Mechanoreceptors on the endothelial cells detect an increased blood flow and secrete vasodilators to bring the blood flow down.
What are the two main vasodilatory molecules? What other effect do they have?
Nitric Oxide: Inhibit aggregation of platelets
Prostacyclin (PGI2): Cardioprotective molecule. Anti-atherogenic
Anti-platelet
What are the three main vasoconstricting molecules?
Thromboxane A2: produced in endothelial cells but also by platelets.
Vasoconstrictor
Pro-atherogenic
Pro-platelet
Endothelin-1
Angiotensin II
What is vascular tone controlled by
it is controlled by the balance of the forces causing vasoconstriction and vasodilation
What is special about endothelin-1?
Endothelin-1 can cause BOTH vasoconstriction AND vasodilation - it has different receptors on different tissues
How is NO produced in the vascular endothelial cell and what are its effects?
- ACh binds to GPCR (G-protein-coupled receptors)
- PLC migrates along membrane
- PLC converts:
PIP2 —-> IP3 + DAG - IP3 triggers Ca2+ influx from ER
- Ca2+ upregulates eNOS (cytoplasmic enzyme = endothelial Nitric Oxide Synthase)
- eNOS converts L-Arg + O2 to L-Cit + NO
- NO diffuses into VSMC and activates GC (guanylyl cyclase)
- GC converts GTP to cGMP
- cGMP upregulates PKG
- PKG activates potassium channels
- Membrane hyperpolarises (negative)
- Cell relaxes
- Vessel dilates
What role does the EFFLUX of calcium play
Calcium efflux reduces tension within the myocyte and stimulates relaxation.
What role does acetylcholine play in blood vessels?
What is the role of phosphodiesterase enzyme in the action of NO?
Acetylcholine UPREGULATES activation of endothelial nitric oxide
This leads to steady vasodilation.
Phosphodiesterase enzyme starts to breakdown cGMP to GMP
Give an example of a nitric oxide donor.
SNP - sodium nitroprusside
Describe how thromboxane A2 and prostacyclin is made
- Phospholipid —————> Arachidonic Acid
Enzyme: Phospholipase A2 - Arachidonic acid ————-> Prostaglandin H2
Enzyme: COX1 ~(cyclooxygenase) + COX2 . - Prostaglandin H2 can then be converted to:
Thromboxane A2 (by Thromboxane Synthase) OR
Prostacyclin (by Prostacyclin Synthase), or PGD2, PGE2, PGF2
which cyclooxygenase is produced more in response to inflammation?
Cyclooxygenase 2 will be upregulated if your body has an inflammatory problem.
Describe how leukotrienes are produced from arachidonic acid.
Lipoxygenase enzymes convert arachidonic acid to: LTA4, LTB4, LTC4 and LTD4
What are the leukotrienes that are produced by the lipoxygenase enzymes and what effect does LTD4 have?
LTA4, LTB4, LTC4 and LTD4
LTD4 causes BRONCHOCONSTRICTION and LTD4 is associated with asthma, therefore bronchoconstriction
What therapy blocks the action of LTD4?
Montelukast Therapy which reduces broncoconstriction helping the patient breathe more comfortably.
how does thromboxane and prostacyclin work?
Prostacyclin
Vasodilator
Anti-atherogenic
Anti-platelet
Thromboxane A2
Vasoconstrictor
Pro-atherogenic
Pro-platelet
This is why thromboxane is typically bad for the cardiovascular system and prostacylin has cardio-protective properties.
What enzyme produces arachidonic acid from DAG?
DAG (diacylglycerol) lipase converts DAG to Arachidonic acid
How is prostacyclin produced and what are its effects?
- PGI2 (prostacyclin) produced via COX1 (and COX2) = cyclooxygenase
- PGI2 diffuses into VSMC
- PGI2 binds to IP (prostacyclin) receptor
- Upregulation of adenylyl cyclase (AC)
- AC converts ATP to cAMP
- cAMP inhibits MLCK
- Reduced cross-bridge cycling
- Cell relaxes
- Vessel Dilates
what effect does prostacyclin have when it is secreted in the blood
it has anti-platelet aggregation properties
Where is thromboxane produced?
Where is thromboxane synthase enzyme mainly found?
- Endothelial Cells
- Platelets
Platelets
What are the two types of receptor for thromboxane and where are they found?
Alpha = Platelets Beta = Smooth Muscle Cell
Describe the mechanism of action of thromboxane on vascular smooth muscle cells.
what happens when thromboxane binds to platelets
Thromboxane binds to Beta receptor on smooth muscle cell and activates PLC
- TXA2 (thromboxane) diffuses through apical and basement membrane
- TXA2 binds to TPβ on VSMC
- PLC migrates along membrane
- PLC converts PIP2 to IP3+DAG
- IP3 triggers Ca2+ influx from extracellular space and SER
- Ca2+ upregulates MLCK
- VSMC contracts
- Vessel constricts
- TXA2 binds to TPα on platelets
- Platelet becomes ‘active’ and produces more TXA2
- Positive feedback potentiates response
- Platelets aggregate
What effect does endothelin-1 have on smooth muscle cells?
CONSTRICTION
What two types of receptors does endothelin-1 have?
Alpha and Beta receptors
How is endothelin-I produced and what are its effects?
Alpha and Beta receptors on smooth muscle are linked to
- Simultaneously causes vasoconstriction and vasodilation ( but not in equal amounts so main effect is vasoconstriction)
- Not produced elsewhere in the body but instead the nucleus of the endothelial cell
- Endothelial nucleus produces Big Endothelin-I (precursor)
- Endothelin-converting enzyme converts zymogen to ET-I
- ET-I binds to ETA and ETB receptors on VSMC
- Receptors release PLC
- PLC converts PIP2 to IP3
- IP3 triggers Ca2+ influx
- Vessel constricts
- ET-I binds to ETB on endothelial cell
- Upregulated eNOS (endothelial nitric oxide synthase)
- Increased NO production
- NO diffuses into VSMC
- Cell relaxes
- Vessel Dilates
What antagonists inhibit the production of endothelial-1 precursor?
Prostacyclin NO Atrial Natriuetic peptide Heparin Hepactocyte growth factor Epidermal growth factor
which agonist stimulate the production of endothelial-1?
Adrenaline
Vasopressin
Angiotensin II
Interleukin-1
How is angiotensin II produced
- Liver produces precursor angiotensinogen
- In the presence of renin (produced by juxtaglomerular cells in the kidney) it is converted to angiotensin I
- Angiotensin I is converted to angiotensin II by ACE (expressed on endothelial cells of the vessels in lungs and kidney and on the endothelial cells of BLOOD VESSELS)
- Angiotensin II then has 5 effects
What effects do angiotensin II have?
Increase Vascular Resistance:
- upregulate sympathetic nervous system = increased vascular resistance/CO/vasoconstriction
- directly interfere with endothelial cells and cause arteriolar vasoconstriction
Increase Water Retention:
- ADH/vasopressin secretion = increased water retention/vasoconstriction
- Aldosterone secretion = effects sodium reabsorption
- directly interfere with the nephron and affecting tubular sodium reabsorption
It leads to increased water retention and vascular resistance this INCREASES BLOOD PRESSURE
Because there’s more volume of fluid and a smaller space for it to travel through
What are the effect of angiotensin II on the endothelial cell?
- Once Ang II is produced (as described above) it diffuses across endothelium to VSMC
- Ang II binds to AT1 receptor
- PLC migrates along membrane
- PLC 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
What other action does ACE have other than converting angiotensin I to angiotensin II?
It breaks down bradykinin
How do we go about increasing the diameter of blood vessels?
Increase NO by:
Stimulate the production of NO
Give an NO donor (e.g. SNP)
What is the mechanism of action of bradykinin on endothelial cells and what effect does it have?
Bradykinin binds to its receptor on endothelial cells.
PLC: PIP2 —-> IP3 + DAG
Results in UPREGULATION OF eNOS —–> increase in NO —–> VASODILATION
what are the ways to increase the amount of nitric oxide and why do we want to do this?
-to increase the diameter of the blood vessels.
DONE BY:
-stimulating the production of nitric oxide
-donating nitric oxide
Stimulation the production of nitric oxide is ENDOTHELIUM-DEPENDANT, and donation of nitric oxide is ENDOTHELIUM-INDEPENDANT.
Describe the mechanism of action of viagra.
NO works by activating guanylyl cyclase, which then converts GTP —> cGMP
The increase in cGMP causes relaxation (vasodilation)
cGMP is eventually broken down by PHOSPHODIESTERASE to GMP
Viagra is a PHOSPHODIESTERASE INHIBITOR
How does aspirin affect the synthesis of prostaglandins?
Aspirin causes irreversible inhibition of COX enzyme
This reduces the conversion of arachidonic acid to prostaglandin H2 and hence decreases production of prostaglandins.
How does aspirin affect COX1 and COX2?
Aspirin causes:
COX1: inactivation
COX2: switches its function ( to generating protective lipid)
What is the effect of low dose aspirin on prostacyclin and thromboxane production?
Maintains high prostacyclin production while decreasing thromboxane production
Why does low dose aspirin have this effect?
Thromboxane is mainly produced by platelets, which have NO NUCLEUS
So the platelets can’t produce more COX. Aspirin irreversibly binds to the COX in the platelets and the platelets can’t make more COX to compensate.
Endothelial cells can make more COX so their prostacyclin levels remains high.
The reduction in Thromboxane (pro-platelet) and increase in Prostacyclin (anti-platelet) means Aspirin has anti-platelet effects
What is the problem with designing calcium channel blockers and what is the solution?
A calcium channel blocker needs to be designed such that it doesn’t interfere with the calcium channels in the heart.
Solution: the affinity of the calcium blocker to the channel is dependent on MEMBRANE POTENTIAL
Smooth muscle cells have a MORE POSITIVE membrane potential than cardiomyocytes
what is the effect of ACE inhibitors
ACE Inhibitors block ACE molecules on the endothelial cell and cause:
Angiotensin-I is NOT converted to Angiotensin-II
As a result Angiotensin-II does NOT bind to the AT-I receptor on the VSMC and contraction does NOT take place
Bradykinin (a vasodilator) is NOT broken down
Instead it binds to the B1 receptor and stimulates production of Nitric Oxide
Therefore, ACE Inhibitors have a vasodilatory effect
