Blood vessel order, function and cell specialisation Flashcards
What are the three layers of blood vessels?
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
What are the function of endothelium?
- 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
What do mechanoreceptors in endothelial cells do?
Detects increased blood flow – secretion of vasodilators
Name 2 types of vasodilators
Nitric Oxide – inhibits platelet aggregation
PGI2 (Prostacyclin) – inhibits platelet aggregation and cardioprotective molecule
Name 3 types of vasoconstrictors
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
What is an example of a stressor that upregulates NO production?
Shear stress force of blood going across the endothelial cells
How does Nitric Oxide work?
- 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)
How does ACh cause vasodilation?
It triggers the upregulation of endothelial nitric oxide - you get steady vasodilation
If the endothelium is destroyed which drug can be given to cause vessel dilation?
SNP – a nitric oxide donor
What is arachidonic acid made from and by what?
Phospholipid can be converted to arachidonic acid by Phospholipase A2
What two things can be made from arachidonic acid?
• 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
What is the role of thromboxane?
- It is a powerful vasoconstrictor and it stimulates platelet aggregation
- It enables the formation of atheromatous plaques
Which receptors does thromboxane bind to?
- Alpha - platelets
* Beta - vascular smooth muscle cells
How does thromboxane lead to vasoconstriction?
- Binds to the beta receptor which is coupled with phospholipase C
- Converts PIP2 to IP3 which results in the constriction of blood vessels
How does thromboxane lead to platelet aggregation?
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
What is the role of prostacyclin?
- Causes vasodilation
- Inhibits the formation of atheromatous plaques
- Stops platelet aggregation
Where is COX 1 expressed?
in all cells
What happens to COX 2 during inflammation?
It will be upregulated
What happens when arachidonic acid follows the leukotriene pathway?
- 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
Where else can arachidonic acid be produced from?
From DAG via DAG lipase
What happens if arachidonic acid is exposed to lipoxygenase?
Goes down the leukotriene route
What happens if arachidonic acid is exposed to COX?
It goes down the prostaglandin route
How does prostacyclin lead to vasodilation?
- 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
Where else is prostacyclin released and what are its effects?
Prostacyclin is also secreted into the blood where it has anti-platelet aggregation properties
Where is endothelin – 1 produced?
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
Where does endothelin -1 bind on smooth muscle?
- Alpha and beta receptors on smooth muscle
* They are bound to PLC which converts PIP2 to IP3 which causes contraction
What happens if endothelin- 1 binds to beta receptors on an endothelial cell?
- 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
Name 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)
Name agonists which stimulate the production of the endothelin-1 precursor
- Adrenaline
- Vasopressin
- Angiotensin II
- Interleukin-1
How does angiotensin lead to vasoconstriction?
- 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)
What is bradykinin and how does ACE affect it?
- 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
To increase blood vessel diameter, what must be increased and how?
• Amount of nitric oxide
• This can be done by:
- Stimulating the production of nitric oxide (endothelium dependent)
- Donating nitric oxide (endothelium independent)
Why would you donate NO to a person with microvascular disease to increase the vessel diameter and decrease blood flow?
Donation of nitric oxide is endothelium-independent
Besides stimulating NO production or donating NO, how can we influence NO?
- 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
What is the mechanism for Nitric Oxide Donors?
- Both endogenous and exogenous NO will activate Guanylyl Cyclase which converts GTP to cGMP
- The cGMP then activates Protein Kinase G which causes relaxation
How does Viagra work?
- cGMP is converted to GMP by Phosphodiesterase
- GMP is metabolically inactive (cGMP normally would activate PKG which causes contraction)
- Viagra is a phosphodiesterase inhibitor
What affect does aspirin have on COX enzymes?
- Aspirin causes irreversible inhibition of the COX enzymes
* (NSAIDs cause reversible inhibition of the COX enzymes)
What effect does aspirin have on COX1 and COX2?
COX1 – inactivation
COX2 - switches its function
Why does reducing arachidonic acid conversion to PGH2 (aspirin) have good and bad effects?
There is a reduce in the amounts of thromboxane (bad)
There is a decrease the production of prostacyclin
Why does low dose aspirin cause prostacyclin level to level off but thromboxane to continue to decrease?
- 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
Why do we have to be careful when blocking calcium channels?
they are found in the heart
How does smooth muscle cell and cardiomyocyte RMP differ? Why is this useful when it comes to calcium channel blockers?
- 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
How can ACE inhibitors be used to cause vasodilation?
- Inhibits the breakdown of bradykinin
* By decreasing the breakdown of bradykinin, it stimulates relaxation because bradykinin has a vasodilatory effect
Why does a damaged endothelium lead to a platelet plug?
- 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
Which drugs involve Gq protein linked receptor (PLC, PIP2, IP3, DAG)?
- Nitric Oxide production
- Thromboxane action
- Endothelin 1 action
- Angiotensin II action
Which drugs involve guanylate cyclase (GTP, cGMP, Protein Kinase G)?
Nitric Oxide action
Which drugs involve adenylate cyclase (ATP, cAMP, Protein Kinase A)?
Prostacyclin action
