Vascular endothelium

Question 1

What does the term endothelium describe? what are its general roles

Answer 1

Simple squamous epithelia lining of blood vessels and associated SMC and ECM
Roles:
Vascular tone, thrombostasis (secrete and metabolise vasocatives
Thrombostasis
absortion and secretion (active transport)
Barrier (prevents pathogens and atheroma
Growth (mediate cell proliferation

Question 2

What are the 5 main key mediators of endothelium?

Answer 2

Nitric oxide, prostacyclin, thromboxane A2, endothelin 1 and angiotensin II

Question 3

How do you assess vacular endithelial function

Answer 3

(dont need to know)
Laser doppler flowmetry-administer ACh and veryfy response of endothelium
Flow mediated dilatation-measure change of diameter with a stimulus (like forarm ischemia (cuff))-increase size as block
not used in clinical practice-observer bias (if on ultrasound)/ position of laser, etc

Question 4

Describe the pathway of arachindonic acid and what it can synthesise from it? How does this relate to aspirin?

Answer 4

Lipids can be made to arachidonic acid by phospholipase A2
Then Cox1/2 makes it into PGH2
From there, depending on enzyme-can make Prostacylin, thromboxane or PGD2PGE2PGF2 (make pain, fever inflamation)-aspirin permanatly inhibits COx1/2 -stops pain but also causes loss of vacular regulation

Question 5

Describe the whole pathway of Nitric Oxide

Answer 5

ACh activation of GCPR -PLC makes DAG and IP3 (from Pip2)
Ip2 release Ca and that signals to eNOS-produce NO (from Larg+02 to Lcit + NO)
No makes it way to SMC-activated Ganylyl cyclase, cGMP activates PKG-activate K channels, membrane hyperpolarise and cell relaxes
Only remember big picture

Question 6

Describe the whole arachnidonic acid pathways and fate of prostacylin

Answer 6

Same as NO, Ach activate PLC-this time noy IP2 but DAG converted by DAG liase to arachidonic acid (then made to PH2, then TXA2, PGI1 and PDG2, pGD2, PGF2 (last 3 are pain)
Prostacylin then moves to receptor-activate adnylyl cylase-cAMP inhibits MLCK-relaxation

Question 7

How does shear stress impact NO, protacylin and thromboxane receptor?

Answer 7

pathways are in other question-but of shear stress is high (or laminar)-then mechanosensors upregulate eNOS activity-vasodilate

Question 8

Recall synthesis of TXA2 and its fate in endothelium

Answer 8

Txa2 made from PGH2 (from arachonic acid (made from DAG or pospholipids)
Binds TPbeta in SMC-activates PLC
IP3 increase Ca2-activates MLCK-SMC contracts

TXA2 also comes to paltelets and activate them-produce more TXA2 -stick to endithelium-good if damage
More expressed in platelets than endothelium

Question 9

Go through the Renin, angiotensin aldosterone (RAS) pathway

Answer 9

Angiotensiongen produced by liver and cleaved by renin (produces by kindey glomerulus) to make Angiotensin I
Lungs and kindeys produce ACE enzyme (membrane bound) that cuts Angio 1 to Angiotensin II-active form
Angiotensin II has 5 function
Increase vasopressin by pit (water retention and vasocontriction)
Upregulate aldosterone secretion by adrenals-increases Na retention (therefore water)
directly increase tubular sodium reaborption (more water (taken with Na)
increase vascular resistance (exite sympathetic nervous system)
AND finally increace arteriolar vasoconstriction

ALL LEAD TO INCREASE BLOOD PRESSURE

Question 10

Describe how angiotensin II acts on vascular endothellial cells (for arteriolar vasocontriction)

Answer 10

Cells have ACE on surface-make ANGI to ANG II
Diffused through endothelium and to SMC
AT1 receptor activates PLC-IP3 and DAG
Ip3 increase Ca release-activate MLCK-constriction
At the same time, ACE degrades bradykinin (opposite effect-normally IP3 increasing NO activation

Question 11

Describe the entire Endithelin I pathway

Answer 11

Produced by nucleus of endothelial cells-as precursor (Big ET1)
Converted to ET1 by Endothelin converting enzyme (ECE)
binds either ETa or ETb (isoforms) on SMC
Both activate PLC-IP3 increase Ca release and constriction
BUT can also go back to endothelial cell-ETb activation of PLC and increase of eNOS activation-dilation (opposite)
Synthesised increased by ANGII, adrnelaine and inhbitied by NO and other

Question 12

What are the 4 main strategies considered to treat hypertension (vasodilate)

Answer 12

inhbite cholesteranse enzymes-increase aCH-can be too complicated
Inhibit phosphodiesterase enzyme (redice NO breakdown-tried but side effects-it made viagra
Medication with a functional NO group-used already but half life is very tight-use as GTN spays (can give headache but good for angina)-too short acting to be usefell
Block flow of Ca (Ca chennels into cells (impede cross bridge)-usually best strategies
Other strats can be ACE inhibitors and angiotensin blockers (effertive as early treatment)

Question 13

Explain the functions of asprinin and consequences of THa2 postracylin and PGD/E/F

Answer 13

2 isoforms of Cox (that makes arachinoid acid to PGD2, etc (pain) and thromboxane and prostacyclin
But aspirin-inhbits Cox1 and stops pain and THA2 BUT NOT prostacylin
Why? because while THA mostly in platelets, prosta mainly in endothelim
Difference is nucleus-endothelium produce more enzyme after it gets destroyed by aspririn, while platelets are deactivated until new ones are made

Question 14

Describe the 3 main layers of endothelium

Answer 14

Tunica adventita-nerves, vasa vasorum
Tunica media-SMC
Tunica intima-enothelium

Question 15

What are the main role of the endothelium

Answer 15

Thrombosis/homeostasis control (with thromboxane, FV, AT, heparin)
Angiogenesis,
Vascular tone (NO, TXA2, Prostacyclin,)
Inflammation (adhesion molecules and inflamatory mediators)

Question 16

What is the main difference between activation and resting endothelium?

Answer 16

Restin is anti-inflam, antithrombo and antiproliferation
Activated, caused by oxLDL, blood pressure, smoking, virus, inflam, mechanical, glucose causes increase in permeability, leukocyte recruit, thrombosis, senescence=>artherosclerosis

Question 17

What are the 10 main stimuli activating endothelium and how

Answer 17

Hypercholestoleamia, High gluc, hypertension, sex hormone imbalance, agein, oxidative stress, inflammation, infections, environemental toxin and heamodynami forces (shear stress)

Question 18

Why does activation of endothelium lead to more leukocyte recruitment

Answer 18

Activation/damage cause upregulation of E and P selectin (rolling), intergins (stopping-on leukocytes cells) and ICAM,VCAM (on endothelium)for diapedisis
HAPPENS IN large arteries in artherosclerosis AS THEY HAVE LESS BM-normally post cappilary venules

Question 19

What are the main factors that cause CHD?

Answer 19

Smoking, raised BP and dyslipedieamia

Question 20

What are the consequences of high LDL for artherosclerosis?

Answer 20

Lipoproteins get trapped in the endothelum and get oxidised. The damage they cause attracts leukocytes, and macrophages to eat it up. But if there is too much, macrophage becomes foam cell-then necrosis and more

Question 21

What are the main characteritics of fatty streaks in artherosclerosis?

Answer 21

SMC migration, Foam cell, T cell activation, Platelet adhesion, leukocyt entry

Question 22

Why does artherosclerosis occur at branch point of arteries?

Answer 22

Because the blood flow isnt laminar there but turbulant
Laminat increases NO, and decreases vasocontriction
Turbulant is pro griwth with AngII, PDGF, ET1, prothrombitic, promigration and no NO

Question 23

What are the 6 main roles of NO?

Answer 23

Reduce LDL oxidation reduce superoxide production, reduce SMC prolif, inhbit monocyte ahdesion, reduce activation of platelets and dilate blood vessels

Question 24

What is the relation between turbulant flow and biochemistry of endothelium activation?

Answer 24

Epigenetic pathway. Laminar flow inhbits DNA methyl transferases- antoatherogenic genes like Klf4 and HoxA5 are on
Turbulant flow, DNMT are upregulated and deactivate klf4 and HoxA5

Question 25

What is angiogenesis and how does it relate to artherosclerosis

Answer 25

Angiogenesis is the formation of new vessels from existing vessels
Usefyk with ischemia, but also happens a lot in plaques-into proliferating SMC and supplies whole plaque

Question 26

What is senecense?

Answer 26

Agein-growth arrest that halt proliferation of ageing/damaged cells

Question 27

What is the role of senecense in artherosclerosis?

Answer 27

Good when it prevents damage transmition and limit cell proliferation
But senescent cells are pro-inflammatory and contribute to endothelium activation
its a response to damage, so increases by other damage

Question 28

What are the main ways to prevent/treat CHD?

Answer 28

Statins, novel therpies. Diet, exercise, homonal balance, miRNA, etc (for exemple, red wine and Reservatol helps)