Vascular endothelium Flashcards
Functions of endothelium
TV BAG
1) Vascular tone management – Secretes and metabolises vasoactive substances.
2) Thombostasis – Prevents clot formation and molecules adhering to the wall.
3) Absorption/Secretion – Allows passive/active transport via diffusion/channels.
4) Barrier – Prevents atheroma development.
5) Growth – Medicates cell proliferation.
Summary table for key mediators (slide 6, lecture 11) Molecule Precursor Enzyme Role of endothelial cell VSMC receptor VSMC 2nd messenger Effects on VSMC Effects on platelets
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Aracidonic acid diagram
(slide 10, lecture 11)
Role?
COX=?
Precursor for TXA2 and PGI2.
- Phospholipase A2 converts phospholipids into Arachidonic Acid.
- Via the COX1 and COX2 enzymes, PGH2 is formed.
- Via different enzymes, TXA2 and PGI2 is formed.
a. Thromboxane synthase → TXA2
b. Prostacyclin synthase → PGI2
COX= cyclooxygenase enzymes
Prostacyclin vs Thromboxane
Prostacyclin= good molecule, keeps cardiovascular system healthy Thromboxane= more likely to be expressed in haemostatic crisis
NO (slide 11, lecture 11) If vessel= smaller, what happens? Exogenous NO? Shear stress increase= ?
1.G-protein coupled receptor is stimulated by ACh
which activates phospholipase C.
2. This converts PIP2 to DAG and IP3.
3. IP3 then stimulates calcium release which activates
eNOS enzyme (also by increased shear stress).
4. eNOS then mediates the reaction:
a. L-arginine + O2 → L-citrulline + NO.
5. NO created passes into the smooth muscle and
activates internal Guanylyl Cyclase to convert GTP
to cGMP.
6. cGMP activates PKG which stimulates relaxation.
If the vessel is smaller, (endothelial: smooth muscle is smaller), has a bigger effect
Exogenous NO can bypass all of this
Shear stress increase= more blood flow along endothelial cells= stimulates more NO because more friction on cell which leads to more relaxation which gives a higher diameter= more throughput
Prostacyclin
(slide 12, lecture 11)
Results in?
Follows the pathway in NO to PGI2 and then…
1. PGI2 binds to the IP receptor on smooth muscle.
2. This activates internal adenylate cyclase which
converts ATP to cAMP.
3. cAMP activates PKA which stimulates vasodilation
Vasodilator, also also results in relaxation alongside other functions (stop platelets aggregating/ clotting factors becoming activated) (friendly molecule)
Thromboxane A2
(slide 13, lecture 11)
Expressed more where?
Follows the pathway to TXA2 and then…
1. TXA2 binds to the TP receptor on smooth muscle.
2. This action converts internal PIP2 to IP3 which
stimulates vasoconstriction.
Moves two ways: into smooth muscle and out into bloodstream
In the smooth muscle cell, binds to thromboxane receptor and is linked to phospholipase C which turns PIP2 into IP3 which causes Ca2+ influx but this causes contraction
Even though same mechanism, Ca released in different cells causes different outcomes
Thromboxame also binds to receptors on platelets which causes change in shape into something more active that causes them to aggregate and to stick to endothelium (beneficial if threre is damage)
Thromboxane expressed more in platelets than smooth muslce
Angiotensin II general
slide 14, lecture 11
- Renin from the kidneys converts angiotensinogen
from the liver into angiotensin I. - ACE then converts Angiotensin I to Angiotensin II.
- Angiotensin II then has effects that:
a. Increase vascular resistance (TPR).
b. Increase water retention. - This results in an increased BP
Angiotensin II pathway
slide 15, lecture 11
ACE converts ANG I into ANG II which breaks through endothelial cell to get to receptors on smooth muscle cells which leads to PLC helping to convert PIP2 into IP3 which leads to Ca influx which causes contraction
Bradykinin which has an opposite effect. Binds to receptor which leads to NO leading to relaxation
ACE also degrades Bradykinin (which inhibits its effect leading to less relaxation): more ACE enzyme present= net effect is contraction
Endothelin I (slide 16, lecture 11)
Vasoconstrictor and dilator.
1. Different hormones (agonists and antagonists) pass
into the nucleus of the endothelial cells.
2. Big-ET-1 is produced by the nucleus which is
converted to ET-1 by ECE enzyme.
3. ET-1 then passes out of the basal layer of the cell.
4. Vasoconstriction:
a. ET-1 binds to ETA and ETB (on VSMC -
PARACRINE) to convert PIP2 to IP3 which
stimulates contraction.
5. Vasodilation:
a. ET-1 has a AUTOCRINE effect and binds to ETB
on endothelial cell.
b. Binding stimulates more eNOS production
which creates more NO for vasodilator
reactions
Simultaneously causes vasoconstriction and vasodialaion
Produced within the nucleus of the endothelial cell and produced as a precursor first. Activated by enzyme on membrane (ECE) which activates it.
Binds to receptors on smooth muscle cell which leads to same mechanism leading to contraction
But can also move backwards onto endothelial cell which upregulates NO synthase (eNOS) leading to relaxation
Antagonists and agonists can influence nucleus
ACE inhibitors+ angiotensin receptor blockers
see slide 17, lecture 11 for more info
Angiotensin Receptor Blockers (ARBs):
Typically, suffixed with –sartsan.
ACE Inhibitors:
Disables endothelial expression of ACE.
Typically, suffixed with –pril.
Calcium Channel Blockers (CCBs):
Disables VGCCs which stops Ca2+ influx for
vasoconstriction.
Typically, suffixed with -dipene.
What can inhibit COX enzymes?
Action of it on each enzyme?
Aspirin= desirable effects if you’re at risk of clotting/ inflamed
COX-1 – Aspirin acetylation inactivates the COX-1 enzyme.
COX-2 – Aspirin acetylation switches COX-2 function to
generating protective lipids.
COX-2-specific inhibitors cause reversible inhibition of COX-2 isoforms only
Other non-specific NSAIDs cause reversible inhibition
Why is prostacyclin more expressed in cells than platelets?
(opposite of thromboxane), because the nucleus in the endothelial cell allows more prostacyclin to be produced (produces more of prostacyclin synthase) compared to a platelet which doesn’t have a nucleus so it doesn’t decrease as much as thromboxane does in the presence of aspirin
Progression of atheroscelrosis
1. Endothelial dysfunction in atherosclerosis Endothelial permeability increases Leukocyte migration Endothelial adhesion Leukocyte adhesion
2. Fatty streak formation in atherosclerosis Foam cell formation T cell activation Platelet adhesion+ aggregation Leukocyte adherence+ entry
3. Formation of an advanced complicated lesion of athersclerosis Macrophage accumulation Fomation of necrotic core Senescence Angiogenesis Fibrous cap formation
Vasa vasorum
Little blood vessels that feed cells in the blood vessels nutrients
