6. Blood Vessel Order, Function and Specialisation of Cells Flashcards
What are the 3 layers of blood vessels and their function?
- Tunica adventitia - external layer containing blood vessles, fibrous tissue, elastin and collagen, helps keep the shape
- Tunica media - predominantly smooth muscle cells - contractions and dilation
- Tunica intima - predominantly vascular endothelium with the elastic basal lamina - exchange surface
What is the basic anatomy and physiology of the heart, arteries, capillaries and veins?
(• structure and function)
• Heart: muscular pump - generate flow
• Arteries: thick muscular walls - stabilise pulsatile flow
• Capillaries: very thin walls - facilitate gas a solute exchange
• Veins: valves - maintain unidirectional flow
What are the 5 functions of the vascular endothelium?
- Vascular tone management - secreting and metabolising vasoactive substances
- Thrombostasis - secretes anti-coagulant substances
- Absorption + secretion - transport via diffusion/channels
- Barrier - prevents entry of bad substances preventing atherosclerosis or further infection
- Growth - mediates cell proliferation
Name 2 important vasodilators (and their functions)
- Nitric Oxide (NO) - inhibits aggregation of platelets
* Prostacyclin (PGI2) - cardioprotective molcule, inhibits aggregation of platelets
Name 3 important vasoconstrictors (and their functions)
- Thromboxane (TXA2) - produced in endothelial cells and platelets, activates other platelets which stimulates aggregation
- Endothelin 1 (ET-1) - can cause vasodilation as well as vasoconstriction as it has different receptors on different tissues
- Angiotensin II (ANG II)
Can vasodilation occur when there’s no endothelium?
- No
- Despite acetylcholine delivery, the endothelium is needed to produce NO for smooth muscle stimulation
- However, an exogenous NO-donor (SNP) can bypass this and cause vasodilation
- Therefore, the endothelial cells don’t need to be relied upon for nitric oxide production
How is arachidonic acid produced?
- Phospholipid (from phospholpid bilayer) => arachidonic acid [phospholipase A2]
- DAG => arachidonic acid [DAG lipase]
What can arachidonic acid be converted into and why is this done?
- Arachidonic acid => Prostaglandin H2 (PGH2) [cyclooxygenase (COX)]
- COX 1 is expressed in all cells
- COX 2 is upregulated if there is an inflammatory problem
- PGH2 is a precursor to a variety of products
- Arachidonic acid => Leukotrienes i.e. LTA4, LTB4, LTC4 & LTD4 [Lipooxygenase Enzyme cascade]
What can Prostaglandin H2 converted into and what are their functions?
- Prostacyclin (PGI2) [Prostacyclin Synthase] - causes vasodilation, inhibits atheromatous plaque formation and stops the aggregation of platelets (cardioprotective)
- Thromboxane A2 (TXA2) [Thromboxane Synthase] - powerful vasoconstrictor and stimulates platelet aggregation (typically bad for CVS)
- Other products involved in pain, fever, inflammation and the health of the epithelia in the GI tract
What is the function of LTD4 and what is Montelukast therapy?
- Bronchoconstriction
- Associated with asthma
- Montelukast therapy can reduce bronchoconstriction
Describe the process from something that stimulates NO production to vasodilation
- Stimulating substance binds to G-protein coupled receptor
- Phospholipase C activated and moves along the membrane
- PLC => IP3 and DAG
- IP3 moves to the endoplasmic reticulum and stimulates calcium efflux
- Rise in calcium upregulates endothelial nitric oxide synthase (eNOS) which converts L-arginine + oxygen => L-citrulline + NO
- NO exits endothelial cell and moves to the vascular smooth muscle cell (VSMC)
- It upregulates the activity of Guanylyl Cyclase which converts GTP => cGMP
- cGMP upregulates Protein Kinase G - activates potassium channels
- Potassium flows in - hyperpolarises the membrane - cell relaxes
What does shear stress do to the VSMCs?
- Stimulator of NO production
* Causes vasodilation to reduce damage due to increased pressure
How does Prostacyclin (PGI2) work?
- Produced by PGH2
- Diffuses into VSMC
- Binds to IP receptor which is coupled to adenylate cyclase (AC)
- AC converts ATP to cAMP
- cAMP upregulates Protein Kinase A, which inhibits Myosin Light Chain Kinase
- Reduces cross-bridge cycling - relaxation
- Vasodilation
• Also secreted into blood - anti-platelet aggregation properties
How does Thromboxane (TXA2) work?
- Diffuses out through both the apical and basement membrane
- Binds to alpha receptor (apical, in platelets) - activation of platelets and production of more thromboxane (positive feedback), domino effect on other platelets, stimulating aggregation until stimulus stops
- Binds to beta receptor (basal, in VSMCs) - coupled with Phospholipase C
- PLC converts PIP2 to IP3 (in VSMCs, unlike the action of NO which produces IP3 in the endothelial cell)
- IP3 triggers calcium influx from extracellular space and SER
- calcium upregulates myosin light chain kinase
- VSMC contracts
How is Angiotensin II produced?
• Renin secreted from kidneys in response to low blood pressure (low renal perfusion)
• Renin cleaves Angiotensinogen to Angiotensin I
• ACE is expressed on endothelial cells in renal/pulmonary circulation:
it converts Angiotensin I to Angiotensin II
What does Angiotensin II do?
Increasing water retention:
• Stimulates ADH secretion
• Increases aldosterone production
• Increases sodium reabsorption
Increasing vascular resistance:
• Increased sympathetic activity (sympathoexcitation)
• Arteriolar vasoconstriction
These both lead to an increase in blood pressure
How does Angiotensin II work in endothelial cells and VSMCs?
- Angiotensin II diffuses across endothelium
- Binds to an angiotensin receptor (AT1) on VSMCs
- This leads to the activation of Phospholipase C
- PLC converts PIP2 to IP3
- IP3 triggers calcium influx from extracellular space and SER
- calcium upregulates myosin light chain kinase
- VSMC contracts
- BP increases
What kind of receptors are AT1?
- Some are G-protein coupled receptors
- Bound to SRC (proto-oncogene) which can upregulate the growth of VSMCs
- Also a mechanism to increase BP
How does bradykinin work and what does ACE do to it?
• ACE breaks down bradykinin
- Bradykinin binds to bradykinin receptor-1
- This activates PLC
- This converts PIP2 to IP3 which upregulates the production of NO in endothelial cells (due to a rise in intracellular calcium)
- NO moves to the VSMC causing relaxation
- Bradykinin has an opposite effect to Angiotensin II
How is Endothelin-1 produced and how does it (mainly) work?
- Endothelin precursor (Big Endothelin 1) is produced in the nucleus of the endothelial cell
- Cleaved by Endothelin Converting Enzyme into Endothelin-1
- Endothelin-1 leaves the cell and binds to alpha or beta receptors, both on the VSMCs
- They are both bound to PLC
- PLC converts PIP2 to IP3
- IP3 triggers calcium influx
- calcium upregulates myosin light chain kinase
- VSMC contracts
- This is the main function due to the greater receptor expression
What happens in endothelin-1 binds to a beta receptor on the endothelial cell?
- Activation of eNOS
- Leads to the production of NO
- NO moves to the VSMC, leading to relaxation
What are the agonists which stimulate the production of Endothelin-1 (precursor)?
- Adrenaline
- Vasopressin
- Angiotensin II
- Interleukin-1
What are the antagonists which inhibit the production of Endothelin-1 (precursor)?
- Prostacyclin
- Nitric Oxide
- ANP (atrial natriuretic peptide)
- Heparin
- HGF (hepatocyte growth factor)
- EGH (epidermal growth factor)
What is the best way to induce the relaxation of VSMCs?
- Block the flow of calcium into cells
- Impedes cross-bridge cycling which is calcium dependent
- Endothelium-dependent
