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Year 2 Cardio > Vascular Endothelium > Flashcards

Vascular Endothelium Flashcards

1
Q

Describe the extent of the vascular system

A

one of the largest and the most extensive networks in the body

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2
Q

What percentage of endothelial cells are in the microvascular system?

A

98%

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3
Q

What is the basic structure of blood vessels?

A

Tunica adventitia
Tunica media
Tunica intimia

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4
Q

What are vasa vasorum?

A

Tiny vessels that feed larger vessels

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5
Q

What is the structure of capillaries and venules?

A

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

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6
Q

What happens in capillaries?

A

exchanges of nutrients and oxygen between blood and tissues occur

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7
Q

What is the function of the microvascuar endothelium?

A

promotes tissue homeostasis

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8
Q

How does the microvascular endothelium promote tissue homeostasis?

A

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

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9
Q

Dysfunctional endothelium contributes to disease more than any other “organ”: give examples of some diseases

A

Ischemia
Chronic inflammatory diseases
Cancer
Diabetes

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10
Q

How is the microvascular endothelium different between systems?

A

Endothelial cells and microvasculature have organotypic (tissue-specific) properties and expression profiles

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11
Q

What is the basic concept of the endothelial cells?

A

Flat
Large surface area
From one cell deep monolayer
Acts as a vital barrier separating blood from tissues

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12
Q

What is contact inhibition?

A

Process that takes place when the junction between to cells come together

The establishment of the junction signals the cell to stop growing

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13
Q

What is the lifespan of endothelial cells?

A

In vivo, endothelial cells live a long life and have a low proliferation rate (unless new vessels are required: angiogenesis)

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14
Q

What are the multiple functions of blood vessels?

A 
Tissue homeostasis and regeneration
Vascular tone 
Angiogenesis
Permeability
Inflammation
Haemostasis & Thrombosis

All controlled by endothelium

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15
Q

What are the products of endothelial cells that regulate thrombosis and haemostasis?

A

Antithrombic factors

Procoagulant factors

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16
Q

What pathways are activated when a trigger is present?

A

Pro-inflammatory
Pro-thrombic
Pro-angiogenic

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17
Q

What triggers can activate endothelium?

A 
Smoking
Viruses
Mechanical stress
Inflammation
High blood pressure
OxLDL
High glucose
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18
Q

How can the endothelium respond to triggers?

A

Thrombosis
Senescence
Permeability
Leukocyte recruitment

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19
Q

What are the products of endothelial cells that regulate angiogenesis?

A

Matrix Products

Growth factors

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20
Q

What are the products of endothelial cells that regulate inflammation?

A

Adhesion molecules

Inflammatory mediators

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21
Q

What are the products of endothelial cells that regulate vascular tone permeability?

A

Vasodilator factors

Vasoconstricting factors

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22
Q

What is the pathogenesis of atherosclerosis?

A

Endothelial dysfunction - activation causes increase in permeability and upregulation of the systems that promote the adhesion of leukocytes

Leukocytes migrate and accumulate in the sub-endothelial space

Phagocytosis of the lipids in the sub-endothelial space leads to

Fatty-streak formation

Formation of necrotic core

Angiogenesis

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23
Q

What stimuli cause atherosclerosis?

A 
Hypercholesterolaemia 
Diabetes Mellitus
Hypertension
Sex hormonal imbalance
Ageing
Oxidative stress
Proinflammatory cytokines
Infectious agents
Environmental toxins
Hemodynamic factors
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24
Q

What are the 4 mechanisms that contribute to the formation of atherosclerotic plaques?

A

Leukocyte recruitment
Permeability
Shear stress
Angiogenesis

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25
Q

What are the steps of the leukocyte adhesion cascade?

A 
Rolling
Activation
Arrest
Adhesion
Transmigration
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26
Q

What is the role of the endothelium in the adhesion cascade?

A

Endothelium expresses molecules that supports the processes of the adhesion cascade

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27
Q

Where does recruitment into tissues normally take place?

A

During inflammation

In post-capillary venules

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28
Q

Where does recruitment of leukocytes 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

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29
Q

What is the function of the endothelium relating to permeability?

A

The endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa

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30
Q

What is the consequence of increased permeability?

A

Increased permeability results in leakage of plasma proteins through the junctions into the subendothelial space

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31
Q

Where do atherosclerotic plaques occur preferentially?

A

Bifurcations and curvatures of the vascular tree

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32
Q

Why do they occur preferentially ?

A

The flow patterns and hemodynamic forces are not uniform in the vascular system

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33
Q

How do straight and curved parts of vessels affect flow?

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.

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34
Q

What does laminar flow promote?

A

It is protective

anti-thrombotic, anti-inflammatory factors
endothelial survival
Inhibition of SMC proliferation
Nitric oxide (NO) production

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35
Q

What does disturbed flow promote?

A

Thrombosis, inflammation (leukocyte adhesion)
endothelial apoptosis
SMC proliferation
Loss of Nitric oxide (NO) production

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36
Q

What are the protective effects of nitric oxide on the cardiovascular system?

A 
Dilates blood vessels
Reduces platelet activation 
Inhibits monocyte adhesion
Reduces proliferation of SMC in the vessel wall
Reduces releases of superoxide radicals
Reduces oxidation of LDL cholesterol
37
Q

What is angiogenesis?

A

The formation of new vessels by sprouting from existing vessels

38
Q

What triggers angiogenesis?

A

Hypoxia

39
Q

What are the steps of angiogenesis?

A

Endothelial cell recepetor binding

EC activation

EC proliferation

Driectional migration

ECM remodelling

Tube formation

Loop formation

Vascular stabilisation

40
Q

What does angiogenesis play a key role in?

A

Embryonic development
Wound healing
Menstrual cycles

41
Q

What are the good and bad outcome of angiogenesis in cardiovascular disease?

A

Bad- angiogenesis promotes plaque growth

Good- therapeutic angiogenesis prevents damage post-ischaemia

42
Q

What are frequent in COVID patients?

A

Venous and arterial thrombosis

43
Q

What does loss of normal antithrombotic and anti-inflammatory functions cause?

A

thrombosis with associated inflammation: thromboinflammation

44
Q

When do you get thromboinflammation?

A

Occurs in many disorders, including sepsis, ischemia-reperfusion injury etc.

45
Q

What does COVID trigger?

A

Cytokine storm
Endothelical activation
Procoagulant switch

46
Q

What are the 2 possible mechanism that covid can cause endothelial damage?

A

Cytokine storm

Directly

47
Q

Does SARS-CoV2 actually bind endothelial cells?

A

Lack of evidence

ACE2 expressed on epithelial not endothelium

48
Q

What research is ongoing?

A

Research into drugs that prevent or reverse endothelial dysfunction are likely to benefit many diseases including COVID

49
Q

What are the modifiable risk factors for atherscelrosis?

A 
Smoking
Lipids intake
BP
Diabetes
Obesity
Sedentary lifestyle

Multiple of the above increase risk greatly

50
Q

What are the non-modifiable risk factors for atherosclerosis

A

Age
Sex
Genetic background

51
Q

What are the recent epidemiological changes relating to atherosclerosis?

A

Reduced hyperlipidaema
Reduces hypertension
Increased obesity and diabetes
Changing pathology of coronary thrombosis

52
Q

How do LDLs contribute to atherosclerosis?

A

Low density lipoproteins (LDL) deposit in the subintimal space and binds to matrix proteoglycans

53
Q

What are the stages of atherosclerosis progression?

A

Lesion prone location- adaptive thickening

Type II lesion - macrophage foam cells

Type III prearthroma - small pools of extracellular lipid

Type IV atheroma - core of extracellular lipid

Type V fibroatheroma - Fibrous thickening

Type VI complicated lesion -Fissure and hematoma and thrombosis

Type VI lesion

54
Q

What is the natural progression of atherosclerosis?

A

Normal
Intermediate lesions
Advanced lesions
Complications

55
Q

What are the main complications of atherosclerosis?

A

stenosis, plaque rupture

56
Q

What are the main cell types involved?

A 
Vascular endothelial cells
Monocyte macrophages
Vascular smooth muscle cells
Platelets
lymphocytes
57
Q

What are the available clinical interventions for atherosclerosis?

A

Secondary prevention
Catheter based interventions
Revascularisation surgery
Treatment of heart failure

58
Q

How was the role of inflammation in atherosclerosis discovered?

A

Patients injected with antibodies to Interleukin 1

Had fewer cardiovascular events

59
Q

What is the death zone?

A

Lipid necrotic core
Dead/dying cells that release cholesterol
Cholesterol crystallizes

60
Q

How can WBCs cause harm?

A

White blood cells can injure host tissue if they are activated excessively or inappropriately!

61
Q

What are the two main classes of macrophage?

A

Inflammatory

Resident

62
Q

What is the function of inflammatory macrophages?

A

Adapted to kill microorganisms (germs)

63
Q

What are the functions of resident macrophages?

A

Normally homeostatic - suppress inflammatory activity

Alveolar resident macrophages - surfactant lipid homeostasis

Osteoclasts - calcium and phosphate homeostasis

Spleen - iron homeostasis

64
Q

What are the characteristics of LDLs?

A

Bad’ cholesterol - Synthesised in liver.
Carries cholesterol from liver to rest of the body including arteries.
But is required in small amounts

65
Q

What are the characteristics of HDLs?

A

Good’ cholesterol

Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)

66
Q

What are oxLDLs and modified LDLs?

A

Oxidation due to action of free radicals on LDL

Not one single substance

Families of highly inflammatory and toxic forms of LDL found in vessel walls

67
Q

How is subendothelial trapped LDL modified?

A

LDLs leak through the endothelial barrier by uncertain mechanisms.

LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer and becomes susceptible to modification

LDL becomes oxidatively modified by free radicals. Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation!

68
Q

What are the features of familial hyperlipidemia?

A

Autosomal genetic disease

Massively elevated cholesterol (20mmol/L).

Failure to clear LDL from blood.

Xanthomas and early atherosclerosis; if untreated fatal myocardial infarction before age 20.

69
Q

What did the discovery of LDL receptor lead to?

A

Cholesterol synthesis is also negatively regulated by cellular cholesterol. Led to the discovery of HMG-CoA reductase inhibitors (= “statins”) for lowering plasma cholesterol.

70
Q

What is the function of Macrophage scavenger receptor A?

A

Known as CD204
Binds to oxidised LDL
Binds to Gram-positive bacteria like Staphylococci & Streptococci
Binds to dead cells

71
Q

What is the function of Macrophage scavenger receptor B?

A

Known as CD36
Binds to oxidised LDL
Binds to malaria parasites
Binds to dead cells

72
Q

What are the functions of activated macrophages?

A

Generate free radicals that further oxidise lipoproteins

Phagocytose modified lipoproteins, & become foam cells

Express cytokine mediators that recruit monocytes

Express chemo-attractants & growth factors for VSMC

Express Proteinases that degrade tissue

73
Q

How do macrophages generate free radicals?

A

Macrophages have oxidative enzymes that can modify native LDL.

a) NADPH Oxidase, for example superoxide O2-.
b) Myeloperoxidase, for example, HOCl hypochlorous acid (bleach) from ROS + Cl-, HONOO Peroxynitrite.

74
Q

How do macrophages phagocytose?

A

Macrophages accumulate modified LDLs to become enlarged foam cells.

75
Q

How do macrophages express cytokine mediators?

A

Plaque macrophages express inflammatory factors that are involved in monocyte recruitment.

Positive feedback loop / vicious cycle leading to self-perpetuating inflammation.

76
Q

What are cytokines?

A

Cytokines – protein immune hormones that activate endothelial cell adhesion molecules

77
Q

What are chemokines?

A

Chemokines - small proteins chemoattractant to monocytes

78
Q

What cytokines do macrophages produce?

A

Interleukin-1 upregulates vascular cell adhesion molecule 1 VCAM-1

VCAM-1 mediates tight monocyte binding

Atherosclerosis is reduced in mice without IL-1 or VCAM-1

79
Q

What chemokines do macrophages produce?

A

Monocyte chemotactic protein-1 (MCP-1)

MCP-1 binds to a monocyte G-protein coupled receptor CCR2.

Atherosclerosis is reduced in MCP-1 or CCR2 deficient mice.

80
Q

How do macrophages promote wound healing?

A

Macrophages release complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit extracellular matrix

81
Q

What chemo-attractants and growth factors do macrophages express?

A

Platelet derived growth factor:

Vascular smooth muscle cell chemotaxis
Vascular smooth muscle cell survival
Vascular smooth muscle cell division

Transforming growth factor beta:

Increased collagen synthesis
Matrix deposition

82
Q

How do macrophages express proteinases that degrade tissue?

A 
Metalloproteinases (=MMPs)
Family of ~28 homologous enzymes.
Activate each other by proteolysis.
Degrade collagen.
Catalytic mechanism based on Zn.
83
Q

What are the characteristics of vulnerable and stable plaques?

A

Large soft eccentric lipid-rich necrotic core

Increased VSMC apoptosis

Reduced VSMC & collagen content

Thin fibrous cap

Infiltrate of activated
macrophages expressing MMPs

84
Q

How can macrophages go through apoptosis?

A

OxLDL derived metabolites are toxic eg 7-keto-cholesterol

Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading.

Once overwhelmed, macrophages die via apoptosis.

85
Q

What do dead macrophages result in?

A

Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core.

Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood.

86
Q

What is Nucleasr Factor Kappa B (NFkB)?

A

Transcription Factor

Master regulator of inflammation

87
Q

How does NFkB work?

A

Switches on numerous inflammatory genes:

Matrix metalloproteinases
Inducible nitric oxide synthase
Interleukin-1

88
Q

What activates NFkB?

A

Activated by numerous inflammatory stimuli:

Scavenger receptors
Toll-like receptors
Cytokine receptors e.g. IL-1

Year 2 Cardio (10 decks)

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