vascular endothelium Flashcards
whats is the basic structure of blood vessels?
endothelium lines the inside
basement membrane behind
then lamina propria (smooth muscle and connective tissue)
then an internal elastic membrane
then a layer of smooth muscle
then an external elastic membrane
them the vasa vasorum (tiny blood vessels that supply bigger blood vessels) and nerves on the outside
it is split into three main layers:
Tunica intima -
Endothelium (up to internal elastic membrane)
Tunica media -
Smooth muscle cells and external membrane
Tunica adventitia -
Vasa vasorum, nerves
what is the structure of capillaries and venules?
formed only by endothelium
supported by some mural cells (pericytes) and a basement membrane
Capillaries is where the exchanges of nutrients and oxygen between blood and tissues occur.
Microvascular endothelium promotes tissue homeostasis -
Damage to the endothelium can cause organ dysfunction
what is the role of the microvasculature in tissue homeostasis?
not just a distribution system (pipes)
Microvascular endothelium is the source of angiocrine factors required for the maintenance of tissue homeostasis and organ regeneration
Dysfunctional endothelium contributes to disease more than any other “organ”: Ischemia Chronic inflammatory diseases Cancer Diabetes
what is tissue specific microvasculature?
blood vessels around the body are not all the same. they are heterogenous
arteries, capillaries and veins are different depending on there they are in the body
= tissue specific microvasculature
eg. differences between heart, liver, lungs, kidneys, brain
what are the types of capillaries?
continuous:
non fenestrated
fenestrated
discontinuous
what are the endothelial cells that line the vascular system like?
The Endothelium acts as a vital barrier separating blood from tissues
Very extensive: surface area > 1000 m2; weight >100 g
Endothelial cells are very flat, about 1-2 µm thick and 10-20 µm in diameter
Formed by a monolayer of endothelial cells, one cell deep (contact inhibition)
In vivo, endothelial cells live a long life and have a low proliferation rate (unless new vessels are required: angiogenesis)
Endothelial cell regulate essential functions of blood vessels
what is contact inhibition?
when endothelial cells come together and form junctions
establishment of these junctions results in the cells saying to eachother, stop growing.
makes it flat
what are the essential functions of blood vessels?
permeability
inflammation
haemostasis and thrombosis
angiogenensis
vascular tone
Tissue homeostasis and regeneration
these are controlled by the endothelium
how does the resting endothelium regulate its homeostasis?
more focus on anti inflammatory, anti thrombotic and anti proliferative pathways
as opposed to pro- pathways
what leads to and are the results of chronic activation of the endothelium?
causes: smoking viruses mechanical stress inflammation high BP OxLDL high glucose
outcomes: ATHEROSCLEROSIS thrombosis senescence permeability leukocyte recruitment
what is the response to injury model of atherosclerosis pathogenesis?
initial injury results in activation of the endothelium
this causes increase in endothelial permeability, which increases systems that result in the adhesions of leukocytes to the endothelium (these should not stick but flow), and migration of these leukocytes into the sub endothelial space
this results in the accumulation of leukocytes here, resulting in foam cell formation
this slowly leads to the formation of advanced, complicated lesions of atherosclerosis, with macrophage accumulation and formation of a necrotic core
it also stimulates angiogenesis in the vasa vasorum
what are the stimuli and risk factors of atherogenesis in endothelial cell dysfunction?
Hypercholesterolaemia Diabetes mellitus / metabolic syndrome Hypertension sex hormone imbalance ageing
oxidative stress proinflamamtory cytokines infectious agents environmental toxins haemodynamic forces
what are the four mechanisms of the pathogenesis of atherosclerosis?
leukocyte recruitment
permeability
shear stress
angiogenesis
how do leukocytes bind to their target?
triggered by various signalling molecules and chemokines
leads to rolling adhesion - look up a photo
how does leukocyte recruitment differ between arteries and venules and cause atherosclerosis?
Recruitment of blood leukocytes into tissues normally takes place during inflammation
leukocyte adhere to the endothelium of post-capillary venules and transmigrate into tissues as venules only have basement membrane and pericytes around them
in arteries it leads to atherosclerosis as , leukocytes adhere to activated endothelium of large arteries and get stuck in the subendothelial space
Monocytes migrate into the subendothelial space, differentiate into macrophages and become foam cells
how does permeability lead to atherosclerosis?
The endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa
Increased permeability results in leakage of plasma proteins through the junctions into the subendothelial space
lipoproteins flow through the arteries and find leaky junctions
they bind to proteoglycans and become oxidated
macrophages also enter the artery walls
they combine with the oxidated lipoproteins and form foam cells
(leukocyte recruitment where leukocytes should go. lipoproteins going through endothelium that should be tight. forms foam cells)
how does shear stress lead to atherosclerosis formation?
Atherosclerotic plaques occur preferentially at bifurcations and curvatures of the vascular tree
The flow patterns and hemodynamic forces are not uniform in the vascular system
In straight parts of the arterial tree, blood flow is laminar and wall shear stress is high and directional
In branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress.
what is the protective effect of laminar flow on the vascular endothelium?
Laminar blood flow (high shear stress) promotes:
anti-thrombotic, anti-inflammatory factors
endothelial survival
Inhibition of SMC proliferation
Nitric oxide (NO) production!!!
Disturbed blood flow (low shear stress) promotes:
Thrombosis, inflammation (leukocyte adhesion)
endothelial apoptosis
SMC proliferation
Loss of Nitric oxide (NO) production
what is the role of nitric oxide?
it is one of the key regulators of vascular function:
dilates blood cells
reduces platelet activation
inhibits monocyte adhesion
reduces smooth muscle cell proliferation
reduces release of superoxide free radicals
reduces oxidation of LDL cholesterol (major component of plaque)
it is very very important
what is angiogenesis?
The formation of new vessels by sprouting from existing vessels
driven by hypoxia
what is the role of angiogenesis on atherosclerosis formation (janus paradox)?
janus paradox:
Angiogenesis promotes plaque growth - in advance plaques, vasa vasorum angiogenesis is stimulated
Therapeutic angiogenesis prevents damage post-ischemia - in MI (occlusion of a coronary artery) angiogenesis downstream of this can prevent the effects of the ischaemia (we dont know how to use this as a treatmne t yet)
what is thrombosis and coagulopathy like in covid 19?
Both venous and arterial thrombi frequent in COVID19 patients
Incidence unknown; variability in reports and data analysis
Coagulopathy (increased D-Dimers, Fibrinogen) correlates with poor prognosis
Anti-thrombotic therapy recommended in all hospitalised patients (recommendation under review)
Local, in situ thrombosis points to endothelial role
Thrombosis in multiple organs at autopsy.
what is thromboinflammation?
Healthy endothelium is anti-thrombotic and anti-inflammatory
loss of the normal antithrombotic and anti-inflammatory functions of endothelial cells causes thrombosis with associated inflammation: thromboinflammation
Occurs in many disorders, including sepsis, ischemia-reperfusion injury and covid 19
sars-CoV2 infection triggers a “cytokine storm”, which activates the endothelium, making it more procoagulant
what are the two potential mechanisms that could cause endothelial damage and activation in Covid-19?
- The “cytokine storm” secondary to SARS-CoV2 infection causes endothelial damage
- SARS-CoV2 enters endothelial cells and causes direct damage
Does the virus bind to and enter endothelial cells?
Is the main SARS-CoV2 receptor ACE2 expressed in endothelial cells?
there is little or confusing evidence for both of these
