vescular endotheium 2 Flashcards
describe the pathogenesis of atherosclerosis
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
describe the endothelium
single layer of cells
grow next to each other
cells talk to each other and send signals
describe the basement membrane
made of ECM proteins - active
send signals
what is in the tunica intima
[endothelium] made of endothelium, basement membrane, lamina propia - sm and connective tissue, internal elastic membrane
what is in the tunica media
[sm cells]
sm and external elastic membrane
what is in the tunica adventitia
vasa vasorum, nerves
are bv consistant
no, they’re different in different places
what are bv mainly composed of
mainly endothelium and caste around
in heart there is more bv than myocytes
what do endothelial cells do
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
describe the regulation of endothelial homeostasis
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
stimuli for endothelial cell dysfunction
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
describe the normal recruitment of leukocytes
leukocytes adhere to the walls of post capillary venuoles
transmigrate into the tissues
describe the recruitment of leukocytes in atherosclerosis
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
how do the leukocytes go through the endothelium
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
which part of leukocyte migration is reversibole
the rolling of leukocytes along the endothelium
what happens if you lack the mechanism for leukocyte migration
disease
mutation in pathway
cant protect from inflammatory stimulation
how can it be used clinically that this pathway is used in disease
drugs can be produced that target it
problem with teh fact that the migration of leukocytes is different in different locations
the drug may have adverse effects in different tissues to what the drug is intended for
how do we know that leukocyte migration occurs
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
how do endothelial junctions form
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
structure of capillary
endothelial cells surrounded by basement membrane and pericapillary cells (pericytes)
structure of post capillary venules
similar to capillary
with more pericytes
what happens when leukocytes migrate through post capillary venules
they chew on the basement membrane and go through to the tissue
what happens when leukocytes migrate through arteris
they get stuck in the basal membrane
never chew through the arteral wall
structure of the artery
3 thick layrs
rich in cells and ECM
endothelium’s role in permeability
regulates t flux of fluids and moleculs from blood to tissues and vice versa
what is caused by increased permeability of the endothelium
oedema
leakage of plasma proteins through the junctions into the subendothelial space
describe the process of lipoprotein trapping
lipoproteins move through th endothelium adn bind to proteoglycans
they are oxidesed
macraphages eat the lipds
this forms foam cells ad fatty streaks
which points in the cardiac system are prone to atherosclerosis
branch points
describe lamina flow
streamlined
outermost layer slow
innermost fast
porotective flow
describe turbulent flow
irregular flow
speed continuously changing in magnitude and direction
promotes coagulation and inflammation
prevent NO
how can endothelial cells sense changes in flow
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
describe the effect of NO
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
what TF are selectively activated for by lamina flow
KFL2 and KLF4
what TF is selectively activated by turbulent flow
NFkB - involved in inflammation
what is epigenetics
functionally relevant
inheritable changes to the genome
that don’t involve a change to the nucleotide sequence which affect gene expression
what are the 3 main epigenetic mechanisms
DNA methylation
histone modification
miRNA
why is epigenetics relevant
new drugs target the epigenetic pathway - especially in cancer
what happens in epigenetics
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
blood flow and epigenetics
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
what is angiogenesis
a way new bv are formed in the body
what triggers angiogenesis
hypoxia, growth factor bind to end of bv and cause growth
involved in disease eg cancer
bad quality of angiogenesis
promotes plaque growth
good quality of angiogenesis
prevent damage post ischemia
angiogenesis reinstate blood vessels and flow to a blocked area - preventing ischemia
describe senescence
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
good affect of senescence
prevent transmission of damage to daughter cells
repilactive senescence - the limited proliferative capacity of cells in human nature
bad affect of senescent cells
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
how can we prevent atherosclerosis
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
effect of resveratrol
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
