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cardioresp > 1B vascular endothelium > Flashcards

1B vascular endothelium Flashcards

1
Q

What proportion of endothelial cells reside in the microvasculature?

A

98%

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2
Q

Describe the structure of all blood vessels (except capillaries and venules)

A

3 layers:

  • Tunica adventitia
  • Tunica media
  • Tunica intima

Smaller vessels are a continuous monolayer of endo cells surrounded by neuro cells. Possibly important in structure of microvasculature.

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3
Q

What is the structure of capillaries and venules?

A

Formed only be endothelium and supported by some mural cells (pericytes) and a basement membrane

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4
Q

What is the function of the endothelium?

A

It acts as a vital barrier separating blood from tissues. Controls multiple functions of blood vessels and tissues:

  • Vascular tone
  • Permeability
  • Tissue homeostasis and regeneration
  • Inflammation
  • Angiogenesis
  • Haemostasis and thrombosis
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5
Q

How are endothelial cells adapted to their function?

A
  • Very extensive: SA >1000M2
  • Cells form a flat monolayer
  • Very thin
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6
Q

What happens in capillaries?

A

The exchange of nutrients and oxygen between blood and tissues

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7
Q

What other purpose than being a distribution system does the microvascular endothelium have?

A

It is the source of angiocrine factors required for maintenance of tissue homeostasis and organ regeneration

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8
Q

What kinds of diseases does dysfunctional endothelium contribute to?

A
  • Ischaemia
  • Chronic inflammatory diseases
  • Cancer
  • Diabetes
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9
Q

What property does the microvascular endothelium have that differs between organs?

A
  • It has organotypic (tissue-specific) properties and expression profiles- they are heterogenous
  • Non-fenestrated endothelium exists in muscle, lungs, skin, BBB
  • Fenestrated endothelium exists in kidney glomerulus, GI tract
  • Discontinuous endothelium exists in liver, marrow sinus
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10
Q

What is contact inhibition?

A
  • When 2 cells come together to form a junction and stop each other from growing
  • Allows the endothelial cells to form a flat monolayer
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11
Q

What do endothelial cells do once they’ve grown?

A

They live a long life and have a low proliferation rate (unless new vessels are required through angiogenesis)

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12
Q

How do endothelial cells regulate the vascular homeostatic balance?

A
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13
Q

Define angiogenesis

A

The formation of new vessels sprouting from existing vessels usually triggered by hypoxia which activates the endothelial cells

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14
Q

What physiological processes is angiogenesis essential for?

A
  • Embryonic development
  • Menstrual cycle
  • Wound healing
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15
Q

What is the Janus paradox of angiogenesis in cardiovascular disease?

A

Angiogenesis promotes plaque growth. However, therapeutic angiogenesis prevents damage post-ischaemia e.g. in MI

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16
Q

Why is angiogenesis important in cancer?

A
  • Small tumours receive oxygen and nutrients by diffusion from host vasculature.
  • Larger tumours require new vessels. Tumour cells secretes angiogenic factors that stimulate neovessel formation by endothelial cells in adjacent vessels: angiogenic switch.
  • Tumour vasculature facilitates growth and metastasis.
  • Anti-angiogenic drugs in the clinic, in combination with chemotherapy, for a number of solid tumours.
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17
Q

What is the link between thrombosis & coagulopathy and COVID-19?

A
  • Both venous and arterial thrombi are frequent in COVID-19 patients
  • Coagulopathy (increased D-dimers, fibrinogen) correlates with poor prognosis
  • Anti-thrombotic therapy recommended in all hospitalised patients
  • Local in situ thrombosis points to endothelial role
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18
Q

How are thrombosis and inflammation linked to the endothelium?

A
  • 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, ischaemia-reperfusion injury etc
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19
Q

What is vW disease?

A

Von Willebrand disease:
- most common hereditary bleeding disorder due to decrease or dysfunction of von Willebrand Factor (VWF)

20
Q

What is VWD characterised by?

A

Mainly by mucosal bleeding
- most forms are mild

21
Q

What is VWD treated by?

A
  • VWF, DDAVP effective in most cases
  • In some VWD
22
Q

Roles of VWF

A
  • Haemostasis
    • VWF mediates platelet adhesion to the subendothelium and platelet aggregation
  • VWF stabilises circulating coagulation Factor VIII
  • Angiogenesis
    • Endothelial VWF controls blood vessel formation (angiogenesis) and integrity.
23
Q

What pathways are on when the endothelium is resting?

A
  • Anti-inflammatory
  • Anti-thrombotic
  • Anti-proliferative
24
Q

What pathways are switched on when the endothelium is activated?

A
  • Pro-inflammatory
  • Pro-thrombotic
  • Pro-angiogenic
25
Q

What factors can trigger chronic activation of endothelium?

A
  • Viruses
  • Smoking
  • Mechanical stress
  • Inflammation
  • OxLDL
  • High bp
  • High glucose
26
Q

What does chronic endothelium activation cause?

A
  • Thrombosis
  • Senescence- ageing of endothelial cells
  • Leukocyte recruitment
  • Permeability
27
Q

Describe the model of pathogenesis of atherosclerosis

A

1) Initial injury results in activation of endothelium

2) This increases endothelial permeability, upregulation of systems that promote leukocyte migration and adhesion

3) Leukocytes move into and accumulate in subendothelial space

4) They phagocytose the lipids in this space to create foam cells

5) This process slowly evolves into an advanced, complicated lesion of atherosclerosis

6) Macrophages accumulate, there’s a formation of a necrotic core and angiogenesis is promoted

28
Q

What are the stimuli/risk factors for endothelial cell dysfunction (the first step of atherosclerosis pathogenesis)?

A

ADIPOSE HHH

  • Ageing
  • Diabetes mellitus/metabolic syndrome
  • Infectious agents (e.g. bacterial endotoxins and viruses)
  • Proinflammatory cytokines e.g. IL-1 and TNF
  • Oxidative stress
  • Sex hormone imbalance (e.g. oestrogen deficiency and menopause)
  • Environment toxins (e.g. cigarette smoke and air pollutants)
  • Hypercholesterolaemia (e.g. oxidatively modified lipoproteins)
  • HTN (e.g. ANG-II and ROS)
  • Haemodynamic forces (e.g. disturbed blood flow)
29
Q

Endothelial dysfunction in the pathogenesis of atherosclerosis: mechanisms

A
  • Leukocyte recruitment
  • Permeability
  • Shear stress
30
Q

What is leukocyte recruitment?

A

When inflammatory agents activate endothelium to express molecules that cause leukocytes to be captured, adhere, roll along endothelium then migrate through cell junctions to reach site of inflammation

31
Q

Where does leukocyte recruitment normally occur?

A
  • In post-capillary venules during inflammation
  • The structure of venules is similar to capillaries except they have more pericytes
32
Q

Where does leukocyte recruitment occur in atherosclerosis?

A
  • 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
33
Q

What does the endothelium regulate and how does increased permeability affect this?

A
  • Endothelium regulates 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
34
Q

What do lipoproteins do when there’s increased vascular permeability?

A
  • Lipoproteins go through bloodstream and find + go through leaky junctions in endothelium
  • They find proteoglycans and get oxidated in subendothelial space
  • Macrophages have come in at this point and they take up the oxidated lipoproteins to form foam cells
35
Q

At what parts of the vascular system are atherosclerotic plaques more likely to occur?

A

At bifurcations and curvatures of the vascular tree

36
Q

Why are atherosclerotic plaques more likely to occur at bifurcations and curvatures of the vascular tree?

A

The flow patterns and haemodynamic forces are not uniform in the vascular tree so vortices in blood form to cause inflammation

37
Q

Which blood vessels bifurcate or are the curvatures of the vascular tree?

A
  • Aortic bifurcation (at the arch)
  • Coronary artery bifurcation
  • Carotid artery bifurcation
  • Iliac arteries
  • Femoral arteries
  • In abdomen
38
Q

How does blood flow differ between straight parts and in branches/curvatures of the vasculature?

A
  • 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
39
Q

What is the effect of laminar blood flow on the endothelium?

A

Laminar blood flow promotes:

  • Anti-thrombotic (e.g. thrombomodulin) and anti-inflammatory factors
  • Endothelial survival
  • Inhibition of SMC (vascular smooth cell) proliferation
  • Nitric oxide production
40
Q

What is the effect of disturbed blood flow on the endothelium?

A
  • Promotes thrombosis and inflammation (leukocyte adhesion)
  • Endothelial apoptosis
  • SMC proliferation
  • Loss of NO production
41
Q

What is the importance of NO in the cardiovascular system?

A

It’s essential for the health of the system:

  • Reduces oxidation of LDL cholesterol (major component in plaque)
  • Dilates blood vessels
  • Reduces platelet activation
  • Reduces release of superoxide radicals
  • Reduces proliferation of SMC in the vessel wall
  • Inhibits monocyte adhesion
42
Q

How does COVID-19 cause endothelial disease by disrupting the normal endothelial functions?

A
43
Q

How does the SARS-CoV2 infection cause severe covid-19 disease through the vasculature?

A
  • The infection causes a cytokine storm which activates endothelium and causes a procoagulant switch
  • Endothelium loses anticoagulant properties to prevent thrombus formation
44
Q

What 2 mechanisms does SARS-CoV2 damage endothelium through?

A

1) The ‘cytokine storm’ secondary to the infection causes endothelial damage

2) The virus enters endothelial cells and causes direct damage

This leads us to the questions:

  • Does the virus actually bind to endothelial cells? no evidence as of rn
  • Is there ACE2 expression in endothelial cells? confusing evidence
45
Q

What does the relation between covid-19 and endothelium mean for covid-19 drugs?

A

Drugs that reduce endothelial activation may be beneficial in COVID19 patients- drug screen is ongoing

cardioresp (15 decks)

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