Vascular Endothelium 1 Flashcards
Relate the anatomy and physiology of the heart
The heart is a muscular pump, this is required to generate flow
Relate the anatomy and physiology of the arteries
The arteries have thick muscular walls to stabilise pulsatile flow
Relate the anatomy and physiology of the capillaries
The capillaries have very thin walls to facilitate gas and solute exchange
Relate the anatomy and physiology of the veins
One-way valves to maintain unidirectional flow
What happens when the physiology changes
The anatomy can also change- seen in angiogenesis.
Describe how blood can act as an endocrine gland
The blood is an important endocrine gland and has evolved to respond to different stimuli.
What is meant by the vascular endothelium
Single cell layer of cells that acts as the blood-vessel interface
It has a multitude of important functions.
Describe the roles of the endothelium
Vascular tone- Secretes & metabolises vasoactive substances (cause smooth muscle contraction or relaxation)
Thrombostasis- Prevents clots forming or molecules adhering to vessel wall
Absorption and secretion- Allows active/passive transport via diffusion/channels
Barrier- Prevents atheroma development & impedes pathogens
Growth- mediates cell proliferation ( angiogenesis or growth of vessels to enable blood to reach blocked area)
Describe the relationship between anatomy and physiology
Bi-directional
What does blood vessel regulation depend on
Downstream forces, local mediators, with the aim of being normotensive and adequately perfusing tissues (pulling and pushing forces are in equilibrium).
What happens in hypertension
Overactive vasoconstrictive mediators.
Explain how we can assess vascular endothelial function using laser Doppler flowmetry
Intact endothelium- add Ach- changes size of micro vessels until plateau is reached.
No endothelium- addition of Ach produces no change in size of micro vessels
Sodium nitroprusside delivery
(exogenous NO-donor)- delivery of Ach changes the size of the micro vessels
What gives blood its colour
Haemoglobin- it is a pigment. Oxyhaemoglobin in arteries- bright red
In veins- dark burgundy
How can flow-mediated dilatation be used to assess vascular endothelial function
Place cuff around forearm, inflate to around 300mm Hg to occlude the brachial artery- observe how the brachial artery increases in diameter
Why aren’t these methods used to assess endothelial function clinically
Observer bias and skill- cross-section of artery in ultrasound, which is 2D, it is hard to locate its position accurately, different positions give different measurements- not strong individually. Too much between-site and observer measurements
Describe the formation of Arachidonic acid
Formed from phospholipids in the plasma membrane, catalysed by Phospholipase A2. Can also be formed by different methods
Explain the further reactions of arachidonic acid
Arachidonic acid is converted into PGH2 (precursor for prostaglandins) by COX1 or COX 2. PGH2 can be converted into Prostacyclin (Prostacyclin Synthase). Thromboxane A2 (Thromboxane synthase) PGD2, PGE2 and PGF2
What else can arachidonic acid be converted into
Leukotrienes (lipoxygenase)
Describe the roles of thromboxane A2
Vasoconstrictor
Pro-atherogenic
Pro-platelet
Released in haemostatic crisis
Describe the roles of prostacyclin
Vasodilator
Anti-atherogenic
Anti-platelet
Describe the roles of PGD2, PGE2 and PGF2
PAIN, FEVER, INFLAMMATION
Describe how nitric oxide can result in relaxation of the smooth muscle
ACh binds to GPCR PLC migrates along membrane PLC converts PIP2 to IP3 (and DAG) IP3 triggers Ca2+ influx from ER Ca2+ upregulates eNOS eNOS converts L-Arginine and O2 into NO and L- citrulline NO diffuses into VSMC & activates GC (Guanylyl cyclase) GC converts GTP to cGMP cGMP upregulates PKG (Protein Kinase G) PKG activates potassium channels Membrane hyperpolarises Cell Relaxes Vessels Dilate
cGMP — GMP by phosphodiesterase
Describe the role of shear stress on the relaxation of vascular smooth muscle
Shear stress stimulates the activity of eNOS, to dilate the vessel and allow more blood to flow through.
Describe the role of prostacyclin on vascular tone
DAG---- Arachidonic acid (DAG lipase) Arachidonic acid --- PGH2 (COX1, 2) PGH2 --- PGI2 (prostacyclin synthase) PGI2 diffuses into VSMC PGI2 binds to IP receptor Upregulation of adenylyl cyclase AC converts ATP to cAMP cAMP inhibits MLCK Reduced cross bridge cycling Cell relaxes Vessel dilates
Describe the role of Thromboxane A2 on vascular tone
TXA2 diffuses through apical and basement membrane
TXA2 binds to TPβ on VSMC
PLC migrates along membrane
PLC converts PIP2 to IP3
IP3 triggers Ca2+ influx from extracellular space and SER
Ca2+ upregulates myosin light chain kinase
VSMC contracts
Vessel Constricts
TXA2 binds to TPα receptor on platelets
Platelet becomes ‘active’ and produces more TXA2
Positive feedback potentiates response
Platelets aggregate
Where is thromboxane synthase more widely expressed
In platelets
Describe the RAAS system
Angiotensinogen — Angiotensin 1 (Renin)
Angiotensin 1 —- Angiotensin 2 (ACE, found in lung and kidney endothelium)
Angiotensin 2 - ADH secretion, Aldosterone secretion, Tubular Sodium Reabsorption (Increasing water retention)
Angiotensin 2- Arteriolar vasoconstriction, sympathoexcitaton (Increased Vascular Resistance)
Increased BP
Outline how angiotensin 2 can result in vasoconstriction
Ang II diffuses across endothelium Ang II binds to AT1 receptor PLC migrates along membrane PLC converts PIP2 to IP3 PLIP3 triggers Ca2+ influx IP3 triggers Ca2+ influx Ca2+ upregulates myosin light chain kinase Cell contracts
ACE metabolises bradykinin
NO-mediated vasodilation is reduced
Vessel constricts
Describe the normal actions of bradykinins
Bradykinin normally binds to B1 receptors on the endothelium, and stimulates NO production via the PLC pathway
Describe the overall effects of endothelin-1
Simultaneously causes vasoconstriction and vasodilation , but is predominantly a vasoconstrictor.
Describe the vasoconstrictor effects of endothelin-1
Endothelial cell nucleus produces Big Endothelin 1
Endothelin converting enzyme converts zymogen to ET-1
ET-1 binds to ETA and ETB receptors on VSMC
Receptors release PLC
PLC converts PIP2 to IP3
IP3 triggers Ca2+ influx
Cell contracts
Vasoconstriction
Describe the vasodilator effects of endothelin-1
ET-1 binds to ETB on endothelial cell Upregulated eNOS Increased NO production NO diffuses into VSMC Cell relaxes Vessel dilates These effects are not equal- net effect is vasoconstriction
List the antagonists for endothelin-1
(PGI2, NO, ANP, heparin, HGF, EGF)
List the agonists for endothelin-1
Adrenaline, ADH, Ang II, IL-1
Which strategy works best to treat hypertension
Preventing the influx of Ca2+ into cells- no effect on heart
Describe other candidates for anti-hypertensive drugs
ACE inhibitors and angiotensin receptor blockers
Describe the difference in the expression of COX-1 and COX-2
COX-1- constitutively expressed
COX-2- expression is upregulated in times of physiological insult
Describe the effect of aspirin on COX-1
Aspirin acetylation inactivates enzyme
Describe the effect of aspirin on COX-2
Aspirin acetylation switches its function (to generating protective lipids)
What is the overall effect of aspirin on the COX enzymes
Aspirin causes irreversible inhibition of COX enzymes
Other non-specific NSAIDs cause reversible inhibition
COX-2-specific inhibitors cause reversible inhibition of COX-2 isoforms only (don’t know how they differ in efficacy or side effects)
Why does aspirin have a greater effect on thromboxane levels than prostacyclin
Thromboxane levels decrease more considerably compared to those of prostacyclin.
Prostacyclin is expressed more in the endothelial cells, whereas thromboxane is expressed predominantly in the platelets.
Platelets have no nucleus and thus cannot synthesis more thromboxane (important to wean patients off aspirin before surgery)
Describe side effects, adverse reactions and drug-drug interactions
Our body often uses the same biochemicals to regulate different processes
Interaction between different systems in the body
Unfortunately, drugs are not always tissue-specific
Receptor expression and distribution varies between tissues
Two people taking the same medicine can have very different experiences
Polypharmacy- people taking too many drugs, interactions with other drugs, genetics and environment
Summarise NO
Precursor (source) L-arginine (diet)
Enzyme - Endothelial nitric oxide synthase (eNOS
Role of endothelial cell- Source of eNOS
VSMC receptor - none
VSMC 2nd messenger - GTP-CGMP (Guanylyl cyclase (GC)
Relaxation of VSMC
Inhibits platelets
Summarise prostacyclin
Precursor (source) - Prostaglandin H2 (arachadonic acid; via COX)
Enzyme- Prostacyclin (PGI2) synthase
Role of endothelial cell- Major source of PGH2
VSMC receptor - IP1
VSMC second messenger - ATP to cAMP
(Adenylyl cyclase (AC)
Causes relaxation of VSMC and inhibition of platelets
Summarise Thromboxane A2
Precursor (source) - Prostaglandin H2 (arachadonic acid; via COX)
Enzyme - Thromboxane synthase
Role of endothelial cell- Major source of PGH2
VSMC receptor - TP1
VSMC second messenger - PIP2 to IP3
(PLC)
Contraction of VSMC and activation of platelets
Summarise endothelin- 1
Precursor (source) - Big Endothelin-1
Enzyme- Endothelin converting enzyme (ECE)
Role of endothelial cell- Precursor source and enzyme source
VSMC receptor - ETA and ETB
VSMC second messenger - PIP2 to IP3(PLC)
Effects of VSMC- Contraction (main) and relaxation
Effects on platelets - none
Summarise angiotensin 2
Precursor (source) - Angiotensin I (Angiotensinogen; via Renin)
Enzyme- Angiotensin converting enzyme (ACE)
Role of endothelial cell- ACE expressed on endothelial cell membrane
VSMC receptor- AT1
VSMC second messenger- PIP2 to IP3
(PLC)
Effects on VSMC- Contraction
Effects on platelets- none
