Endothelium Flashcards
What is the function of the endothelium?
control vascular tone via vasoconstriction and vasodilation
control blood clot formation
angiogenesis
passage of materials in and out of the bloodstream
- is a semi-permeable barrier
regulation of inflammatory reactions
What is the pathophysiology of the endothelium?
lumen - contains red blood cells, etc
basement membrane - provide structural integrity and support, anchor connective tissue to the endothelium
endothelial cells - have different morphologies (flattened, elongated)
pericytes
smooth muscle cells
What are the vasoconstrictive and vasodilatory factors?
vasoconstrictive
- thromboxane A2
- endothelin-1
vasodilatory
- nitric oxide
- prostacyclin
- endothelium derived hyper polarising factor
- angiotensin 2
How does nitric oxide induce relaxation in the vascular smooth muscle cells?
an agonist binds to GqPCR
- agonists = bradykinin, acetylcholine, ATP, substance P
activates phospholipase C (PLC) which metabolises PIP2 into IP3 and DAG
IP3 and DAG induce calcium influx from the SR and ECF
calcium binds to calmodulin forming a Ca-CaM complex
Ca-CaM complex bind to eNOS causing its activation by detaching it from the caveolin
eNOS converts L-arginine to L-citrulline and NO
NO diffuses across the endothelial cells into the VSMC
NO binds to soluble guanylyl cyclase increasing the rate of conversion of GTP into cGMP
cGMP causes vasodilation
How does cGMP cause vasodilation?
acts directly
- inhibits calcium entry into the cell
- reduces calcium release from the SR
- increases calcium reuptake into the SR
activates protein kinase G
- increases potassium efflux = hyperpolarisation
How does shear stress induce NO release?
1st method
shear stress can activate eNOS via the PI3-K pathway and PKB activation
an agonist binds to receptor tyrosine kinase (RTK)
triggers the activation of PI3-K and the conversion of PIP2 to PIP3
PKB binds to PIP3 at the plasma membrane
- allows PDK1 to phosphorylate PKB causing its activation
PKB then activates eNOS via phosphorylation
How can shear stress induce NO release?
2nd method
shear stress activates specialised Ca activated K channels
- there is an influx of calcium and an efflux of potassium
calcium binds to calmodulin forming a Ca-CaM complex
Ca-CaM complex binds to eNOS causing its activation by detaching it from the caveolin
What is L-NAME? When investigating endothelial function what is the effect of L-NAME?
L-NAME is an analogue of L-arginine
- it competes with it for the substrate
reduces relaxation
inhibits acetylcholine induced relaxation
What are prostanoids? What is the effect of prostanoids on the endothelium?
prostanoids - prostaglandins, thromboxane and prostacyclin
TXA2
- binds to TP receptors on VSMC causing vasoconstriction
= increases intracellular calcium
PGI2
- binds to IP receptors on VSMC causing vasodilation
= activates AC, cAMP and PKA which are vasodilatory in VSMCs
What is endothelin-1? What is the effect of endothelin-1 on the endothelium?
endothelin-1 is formed in the endothelium by conversion of BIG ET-1 into ET-1 by endothelin converting enzyme (ECE)
ET-1 binds to Eta or ETb receptors causing vasoconstriction
- opening of calcium channels and influx of calcium
inhibited by NO and PGI2
produced and released by inflammatory cells
What is angiotensin II? What is the effect of angiotensin II on the endothelium?
angiotensin I is converted to angiotensin II by angiotensin converting enzyme (ACE)
angiotensin II binds to angiotensin I receptors causing an increase in endothelin converting enzyme activity
can be inhibited by angiotensin receptor blockers
What is the clinical use of nitric oxide?
are used as nitrovasodilators
- donate NO when broken down in the body
organic nitrates increase cGMP levels intracellularly via the action of soluble guanylyl cyclase
are used for
- angina
- congestive heart failure
- hypertensive emergencies
- pulmonary hypertension
Why is the physiology of the endothelium important in drug administration?
is important for the passage of materials in and out of the bloodstream
routes of administration include
- paracellular = passage between cells
- transcellular = passage through the cell
What can endothelial dysfunction result in?
development of
- prothrombotic
- profibrinolytic
- proinflammatory
- vasoconstrictive
How does hydrogen peroxide (H2O2) modify and activate protein kinase G?
PKG1 alpha can exist as either monomers or dimers in the cardiovascular system
in the presence of hydrogen peroxide, they form dimers
- two monomers bind together through the formation of a disulphide bridge/bond between their cysteine 42 amino acids
hydrogen peroxide activates PKG by oxidising it
- oxidation of PKG involves the removal of a hydrogen atom from each of the monomers and the formation of disulphide bond in their place
