vascular endothelium

Question 1

whats is the basic structure of blood vessels?

Answer 1

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

Question 2

what is the structure of capillaries and venules?

Answer 2

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

Question 3

what is the role of the microvasculature in tissue homeostasis?

Answer 3

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

Question 4

what is tissue specific microvasculature?

Answer 4

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

Question 5

what are the types of capillaries?

Answer 5

continuous:
non fenestrated
fenestrated

discontinuous

Question 6

what are the endothelial cells that line the vascular system like?

Answer 6

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

Question 7

what is contact inhibition?

Answer 7

when endothelial cells come together and form junctions

establishment of these junctions results in the cells saying to eachother, stop growing.

makes it flat

Question 8

what are the essential functions of blood vessels?

Answer 8

permeability

inflammation

haemostasis and thrombosis

angiogenensis

vascular tone

Tissue homeostasis and regeneration

these are controlled by the endothelium

Question 9

how does the resting endothelium regulate its homeostasis?

Answer 9

more focus on anti inflammatory, anti thrombotic and anti proliferative pathways

as opposed to pro- pathways

Question 10

what leads to and are the results of chronic activation of the endothelium?

Answer 10

causes: 
smoking
viruses
mechanical stress
inflammation
high BP
OxLDL
high glucose

outcomes: 
ATHEROSCLEROSIS
thrombosis
senescence 
permeability
leukocyte recruitment

Question 11

what is the response to injury model of atherosclerosis pathogenesis?

Answer 11

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

Question 12

what are the stimuli and risk factors of atherogenesis in endothelial cell dysfunction?

Answer 12

Hypercholesterolaemia 
Diabetes mellitus / metabolic syndrome
Hypertension 
sex hormone imbalance
ageing

oxidative stress
proinflamamtory cytokines
infectious agents
environmental toxins
haemodynamic forces

Question 13

what are the four mechanisms of the pathogenesis of atherosclerosis?

Answer 13

leukocyte recruitment

permeability

shear stress

angiogenesis

Question 14

how do leukocytes bind to their target?

Answer 14

triggered by various signalling molecules and chemokines

leads to rolling adhesion - look up a photo

Question 15

how does leukocyte recruitment differ between arteries and venules and cause atherosclerosis?

Answer 15

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

Question 16

how does permeability lead to atherosclerosis?

Answer 16

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)

Question 17

how does shear stress lead to atherosclerosis formation?

Answer 17

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.

Question 18

what is the protective effect of laminar flow on the vascular endothelium?

Answer 18

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

Question 19

what is the role of nitric oxide?

Answer 19

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

Question 20

what is angiogenesis?

Answer 20

The formation of new vessels by sprouting from existing vessels

driven by hypoxia

Question 21

what is the role of angiogenesis on atherosclerosis formation (janus paradox)?

Answer 21

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)

Question 22

what is thrombosis and coagulopathy like in covid 19?

Answer 22

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.

Question 23

what is thromboinflammation?

Answer 23

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

Question 24

what are the two potential mechanisms that could cause endothelial damage and activation in Covid-19?

Answer 24

1. The “cytokine storm” secondary to SARS-CoV2 infection causes endothelial damage
2. 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