vescular endotheium 2

Question 1

describe the pathogenesis of atherosclerosis

Answer 1

occurs when the endothelium of a large vessel receive chronic stimulation eg from smoke - chronic activation of the endothelial cells
leukocytes attach and accumulate uder the endothelium
permeability increases and lipids also accumulate under the endothelium - causing foam cells
the macrophages die
complex atherosclerotic plaque is formed

Question 2

describe the endothelium

Answer 2

single layer of cells
grow next to each other
cells talk to each other and send signals

Question 3

describe the basement membrane

Answer 3

made of ECM proteins - active

send signals

Question 4

what is in the tunica intima

Answer 4

[endothelium] made of endothelium, basement membrane, lamina propia - sm and connective tissue, internal elastic membrane

Question 5

what is in the tunica media

Answer 5

[sm cells]

sm and external elastic membrane

Question 6

what is in the tunica adventitia

Answer 6

vasa vasorum, nerves

Question 7

are bv consistant

Answer 7

no, they’re different in different places

Question 8

what are bv mainly composed of

Answer 8

mainly endothelium and caste around

in heart there is more bv than myocytes

Question 9

what do endothelial cells do

Answer 9

matrix proteins and growth factors involved in angiogenesis 
thrombosis and haemostasis 
angiogenesis 
vascular tone permeability 
inflammation 

control many processes, there is a balance between pro and anti effects, essential but it is regulated

Question 10

describe the regulation of endothelial homeostasis

Answer 10

at rest there is a tilt towards antiinf, antithrombotic and anti-proliferative
there are time when the balance needs to tilt eg in chronic disease, the endothelium is chronically activated this is permananet
use transcriptional and proteomic screening to assess this

Question 11

stimuli for endothelial cell dysfunction

Answer 11

hypercholesterolaemia (oxidatively modified lipoproteins)
DM - produce radicals
hypertension (ANG2 and ROS)
sex hormone imbalance (oestrogen deficiency and menopause)
aging
oxidative stress
proinflammatory cytokines (IL-1 and TNF)
infectious agents (bacterial endotoxins and viruses)
mechanical stress
high glucose

Question 12

describe the normal recruitment of leukocytes

Answer 12

leukocytes adhere to the walls of post capillary venuoles

transmigrate into the tissues

Question 13

describe the recruitment of leukocytes in atherosclerosis

Answer 13

leukocytes adhere to the endothelium of larger arteries
find the thick wall
and get stuck in the subendothelial spac
monocytes migrate into the subendothelial space and mature into macrophages
newly formed post capillary venules at the base of the developing lesions provide a further portal for leukocyte entry

Question 14

how do the leukocytes go through the endothelium

Answer 14

there are addition molecules on the surface of endothelium

when there is an inflammatory trigger the endothelium present the molecules and the leukocytes bind and go through

Question 15

which part of leukocyte migration is reversibole

Answer 15

the rolling of leukocytes along the endothelium

Question 16

what happens if you lack the mechanism for leukocyte migration

Answer 16

disease
mutation in pathway
cant protect from inflammatory stimulation

Question 17

how can it be used clinically that this pathway is used in disease

Answer 17

drugs can be produced that target it

Question 18

problem with teh fact that the migration of leukocytes is different in different locations

Answer 18

the drug may have adverse effects in different tissues to what the drug is intended for

Question 19

how do we know that leukocyte migration occurs

Answer 19

use intra-vital microscopy
on the stage there is an animal with exteriorised tissue
you can see the movement of leukocytes through capillaries and entering the endothelium

Question 20

how do endothelial junctions form

Answer 20

endothelial cells are a singl aer of clls
when they contact each other during divison, they stop dividing - contact inhibition
interact with molecular pathways
endothelial cells dont divide very much - but they have a long life
you can see the lines at the cell junction by using an Ab to a molecule at that junction

Question 21

structure of capillary

Answer 21

endothelial cells surrounded by basement membrane and pericapillary cells (pericytes)

Question 22

structure of post capillary venules

Answer 22

similar to capillary

with more pericytes

Question 23

what happens when leukocytes migrate through post capillary venules

Answer 23

they chew on the basement membrane and go through to the tissue

Question 24

what happens when leukocytes migrate through arteris

Answer 24

they get stuck in the basal membrane

never chew through the arteral wall

Question 25

structure of the artery

Answer 25

3 thick layrs | rich in cells and ECM

Question 26

endothelium's role in permeability

Answer 26

regulates t flux of fluids and moleculs from blood to tissues and vice versa

Question 27

what is caused by increased permeability of the endothelium

Answer 27

oedema | leakage of plasma proteins through the junctions into the subendothelial space

Question 28

describe the process of lipoprotein trapping

Answer 28

lipoproteins move through th endothelium adn bind to proteoglycans they are oxidesed macraphages eat the lipds this forms foam cells ad fatty streaks

Question 29

which points in the cardiac system are prone to atherosclerosis

Answer 29

branch points

Question 30

describe lamina flow

Answer 30

streamlined outermost layer slow innermost fast porotective flow

Question 31

describe turbulent flow

Answer 31

irregular flow speed continuously changing in magnitude and direction promotes coagulation and inflammation prevent NO

Question 32

how can endothelial cells sense changes in flow

Answer 32

lamina flow promotes antithromboytic, antiinf factors and NO production, inhibits SMC proliferation turbulent flow promotes coagulation, leukocyte adhesion, SNC proliferation, endothelial apoptosis and reduced NO production profile of genes and proteins are regulated by blood flow

Question 33

describe the effect of NO

Answer 33

key regulator in cardiovascular health reduce oxidation of LDL cholesterol - component of plaque reduces the release of superoxide radicals reduce proliferation of SMC in the vessel wall inhibit monocyte adhesion reduces platelet activation dilates BV

Question 34

what TF are selectively activated for by lamina flow

Answer 34

KFL2 and KLF4

Question 35

what TF is selectively activated by turbulent flow

Answer 35

NFkB - involved in inflammation

Question 36

what is epigenetics

Answer 36

functionally relevant inheritable changes to the genome that don't involve a change to the nucleotide sequence which affect gene expression

Question 37

what are the 3 main epigenetic mechanisms

Answer 37

DNA methylation histone modification miRNA

Question 38

why is epigenetics relevant

Answer 38

new drugs target the epigenetic pathway - especially in cancer

Question 39

what happens in epigenetics

Answer 39

the genome adapts to developmental/environmental cues through modification of the DNA - by methylation, or modifying histones essential for development and differntiations twins have different responses to heritable diseases

Question 40

blood flow and epigenetics

Answer 40

blood flow regulates chromatin mechanoreceptor recognises the flow changes the chromatin TF is activated eg stable flow downregulates the expression of DNA methyltransferases - allows promotor of antitherogenic genes to remain demethylated - enabling expression in disturbed flow - upregulate DNA methyltransferases - hypermethylation of antiatherogenic genes - Klf4 and Hox A5 - repressing their expression

Question 41

what is angiogenesis

Answer 41

a way new bv are formed in the body

Question 42

what triggers angiogenesis

Answer 42

hypoxia, growth factor bind to end of bv and cause growth | involved in disease eg cancer

Question 43

bad quality of angiogenesis

Answer 43

promotes plaque growth

Question 44

good quality of angiogenesis

Answer 44

prevent damage post ischemia | angiogenesis reinstate blood vessels and flow to a blocked area - preventing ischemia

Question 45

describe senescence

Answer 45

growth arrest that halts the proliferation of aging anmd or damaged cells it is a response to stress or damage they have distinctive morphology and markers eg b-gal

Question 46

good affect of senescence

Answer 46

prevent transmission of damage to daughter cells | repilactive senescence - the limited proliferative capacity of cells in human nature

Question 47

bad affect of senescent cells

Answer 47

pro-inflammatory and contribute to disease found in atherosclerotic lesions can be induced by CVD risk factors proinf and prothrombotic phenotype may contribute to plaque progression and complications

Question 48

how can we prevent atherosclerosis

Answer 48

Ab used against atherosclerosis caused a drop in CVD stop the 'bad' pathways easier but look into ways to maintain the 'good' pathways good health in general eg diet, exercise, statins, novel therapies

Question 49

effect of resveratrol

Answer 49

``` protective effect on CVD promotes eNOS reduce senescence prevent proinflammatory changes improve function in T2DM beneficial at lower doses and cytotoxic at higher doses clinical benefits not been demonstrated ```