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PMY2106 Medicinal Substances > Angiogenesis > Flashcards

Angiogenesis Flashcards

1
Q

Describe endothelial cells.

A
  • cuboidal cells which line all blood vessels
  • have a surface area of 6000m2
  • divide rarely in adult life
  • capable of rapid division to specific stimuli
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2
Q

What is the main function of the cardiovascular system?

A

Role in transport of nutrients, metabolites, chemical mediators and waste products to and from cells. Role in gas exchange and important for immune system, homeostasis and body control.

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3
Q

What do vasculogenesis and angiogenesis do?

A

Form new blood vessels.

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4
Q

What are mural cells?

A

These are vascular smooth muscle cells and pericytes of the microcirculation.

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5
Q

What is the definition of vasculogenesis?

A

Vasculogenesis is defined as the differentiation of precursor cells called angioblasts into endothelial cells and the de novo formation of a primitive vascular network.

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6
Q

When does vasculogenesis occur?

A

Occurs during embryogenesis.

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7
Q

What is angiogenesis?

A

It is the formation of vascular sprouts from pre-existing vessels resulting in a highly branched vascular plexus.
The primary plexus is remodeled several times until a mature vascular system consisting of vessels of different diameters and functions are formed.

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8
Q

When does angiogenesis occur?

A

During development and postnatal life.

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9
Q

Give examples of angiogenesis occurring normally.

A
  • during reproduction when blood vessels grow in the placenta.
  • thickening of the endometrium in the uterus during menstruation.
  • wound healing.
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10
Q

The healthy body controls angiogenesis through a series of “on” and “off” switches. What are the main on and off switches?

A

The main on switches = angiogenesis stimulating growth factors.
The main off switches = angiogenesis inhibitors.
Angiogenesis is turned off by the production of more inhibitors than stimulators.

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11
Q

How are pro-angiogenic processes switched off?

A

By upregulating anti-angiogenic factors.

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12
Q

Give some examples of pro-angiogenic factors.

A 
VEGFs - vascular endothelial growth factors
FGFs - fibroblast growth factors
Angiopoietins 
PDGF - platelet derived growth factor
TGF Beta - transforming growth factor B
TNF Alpha
CXC Chemokines
EGF - epidermal growth factor
CSF
Insulin
Erythropoietin 
Integrins
MMPs
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13
Q

Give some examples of anti-angiogenic growth factors.

A 
Endostatin
Angiostatin
Soluble FLT1
Tumstatin
PEDF - pigment epithelium derived factor
Platelet factor 4
Alphastatin
Canstatin
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14
Q

What is the consequence of an injury?

A

Causes pro-angiogenic signaling mediators to be activated and their expression gets upregulated.

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15
Q

List some pathologies caused by upregulated angiogenesis.

A 
Diabetic retinopathy
Rheumatoid arthritis 
Atherosclerotic plaques
Endometriosis
Crohn's disease
Psoriasis 
Uterine fibrosis
Benign prostatic hypertrophy
Cancer
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16
Q

Name two degenerative retianal diseases

A

AMD - age-related macular degeneration

Diabetic retinopathy

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17
Q

What is neovascularisation?

A

Formation of new blood vessels.

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18
Q

What is the difference between dry and wet AMD?

A

Dry AMD = the slow deterioration of the cells of the macula over many years as the retinal cells die off and are not renewed.
Wet AMD = presence of blood vessels which invade the retina, this neovascularisation causes irregular and immature blood vessels which leak, leading to the occlusion of the retina - leads to blindness.

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19
Q

The walls of coronary arteries are usually free from micro-vessels. But micro-vessels are present in atherosclerotic plaques. Describe the micro-vessels in the plaques.

A

Atherosclerotic plaques have dense networks of capillaries called vasa vasorum. These micro-vessels can cause hemorrhages - lead to blood clotting - decreased blood flow to heart muscle - results in heart attack.

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20
Q

How does angiogenesis contribute to plaque formation?

A

When blood vessels become thickened, hypoxia occurs in the area. This is a stimulus which switches on angiogenic processes. The thickened blood vessels start to make fragile micro vessels in order to supply oxygen to the area. these micro vessels are not matured and hence leak leading to clot formation.

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21
Q

What pro-angiogenic factors do endometriosis patients have?

A
  • Elevated levels of vascular endothelial growth factor A (VEGF-A)
  • Soluble vascular endothelial growth factor receptors 1 and 2 (VEGF-1 and VEGF-2)
  • Angiopoietin 2 (Ang2)
  • IL-4 = may induce angiogenesis
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22
Q

What happens during endometriosis?

A

Usually during normal menstruation the lining of the womb thickens but in endometriosis the lining starts to thicken outside of the womb. This is a painful condition. In bad endometriosis, lesions can cause tubal and ovarian adhesions.

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23
Q

What is Crohn’s disease?

A

This is a chronic inflammatory condition that affects both small and large intestines, resulting in extensive inflammation and ulceration of the colon. Soluble angiogenic factors are shown to be increased in Crohn’s disease patients.

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24
Q

Describe briefly, tumour angiogenesis.

A

Cancer is an angiogenic-dependent process. A growing tumpur needs an extensive vascular network to provide nutrients and oxygen. The new intratumoural blood vessels allows tumour cells to enter the circulation and to metastasize surrounding organs.

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25
Q

How much can the tumour grow without oxygen and blood supply?

A

Maximum 2mm because that is the distance oxygen can diffuse.

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26
Q

What is the signal that stimulates angiogenesis in tumour cells?

A

After 2mm of maximum growth without oxygen, the core cells of the tumour become hypoxic which is a signal that stimulates angiogenesis to take place. New blood vessels can then form and provides tumour cells with a mechanism to allow them to move throughout the body.

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27
Q

Explain the 20 step process of angiogenesis.

A
  1. Angiogenic factor production, produced by the cells with demand.
  2. Release of angiogenic factors from cells with metabolic demand.
  3. Binding of angiogenic factors to endothelial cell receptors, activating endothelial cells.
  4. Release of proteases from activated endothelial cells and degradation of the basement membrane surrounding the existing vessel.
  5. Endothelial cell proliferation.
  6. Directional migration of the endothelial cells into the interstitial space so that the newly forming blood vessel is now growing towards the cells with metabolic demand.
  7. Extracellular matric remodeling and maturation of the tube - at the leading edge, the migrating cells release factors which breakdown the basement membranes to allow this blood vessel to protrude and grow out to cells with demand.
  8. Lumen formation.
  9. Fusion of newly formed vessels into loops - remodeling the primary blood vessels into mature ones. The blood begins to flow.
  10. Stabilisation by generation of new basement membranes with the recruitment of pericytes.
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28
Q

Why is the recruitment of pericytes important in the maturation process?

A

Pericytes will secrete basement membrane which helps to form and stabilise new blood vessels.

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29
Q

List the key pro-angiogenic factors.

A

Vascular endothelial growth factor (VEGF)
Angiopoietin 1
Basic fibroblast growth factor (FGF2)
Platelet derived growth factor (PDGF)

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30
Q

Where is VEGF expressed?

A

In many tissues, brain, kidney, liver, spleen and by many cell types.

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31
Q

What role does VEGF play in vivo?

A

VEGF regulates vascular permeability which is important for the initiation of angiogenesis.

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32
Q

What is the consequence of the loss of a single allele of VEGF?

A

Leads to embryonic lethality therefore plays an irreplaceable role in the vascular system.

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33
Q

What is VEGF levels regulated by?

A

Regulated by tissue oxygen tension.

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34
Q

Note

Hypoxic upregulation of VEGF -

A
  • provides a mechanism by which tissues or tumours can increase their oxygenation through induction of blood vessel growth.
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35
Q

What is normoxia and wwhat is its effect?

A

Normal/high levels of oxygen - downregulation production of VEGF.

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36
Q

What VEGF receptors are found on vascular endothelium?

A

There are two high affinity tyrosine-kinase receptors for VEGF - VEGFR-1 and VEGFR-2

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37
Q

What is VEGF receptor expression regulated by?

A

Hypoxia

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38
Q

Describe angiopoietins and their functions.

A

Angiopoietins are from a family of proteins that are soluble mediators.
It has a role in blood vessels development, stability and maturation.

39
Q

What receptors do angiopoietins bind to?

A

Endothelial cell specific receptors - tyrosine kinase with immunoglobulin and endothelial growth factor (EGF) like receptors.
Tie-1 and Tie-2

40
Q

What are Tie-2 receptor ligands?

A

Ang-1 and Ang-2 BUT only binding of Ang-1 causes signal transduction and maturation.

41
Q

What are the receptors for FGF-2?

A

Two types - high affinity tyrosine-kinase FGF receptors (FGFRs) and low affinity heparan sulfate proteoglycans (HSPGs)

42
Q

What does FGFR activation cause?

A

Triggers intracellular signaling cascade leading to endothelial cell proliferation and migration, differentiation, protease production and angiogenesis.

43
Q

Describe PDGF growth factor.

A

PDGF comprises of 4 different polypeptide chains which are inactive in their monomeric form and requires a homodimer for the polypeptide to be in its active form.

44
Q

What is the receptor for PDGF?

A

Tyrosine kinase receptor - PDGF-Beta Receptor

45
Q

What role does PGDF play?

A

Associated with angiogenesis. Through the stimulation and activation of the endothelial cells and release of pro-angiogenic factors through the proliferation and migration of the endothelial cells and remodeling of the extracellular basement membrane.

46
Q

How can you differentiate between mature and immature blood vessels?

A

Immature blood vessels are leaky and irregularly shapes.

Mature blood vessels have a larger diameter, uniform in size and shape and not leaky.

47
Q

Why is basement membrane breakdown by proteolysis necessary?

Degradation of the underlying basement membrane and invasion of the stroma of the surrounding tissue

A

To begin formation of new capillary sprouts.

48
Q

What two things are required for proteolytic breakdown of basement membrane in angiogenic process?

A

Requires the activity of urokinase-plasminogen activator (uPA) and the matric metalloproteases (MMPs) enzyme systems.

49
Q

What conversion activates proteolysis?

A

Conversion of plasminogen to plasmin activates proteolysis

50
Q

What inhibits the action of MMPs?

A

Tissue inhibitors of matric metalloproteases (TIMP).

- degradation of the extracellular matrix is dependent on the balance of activity between MMP and TIMP.

51
Q

Tumour cells can also release stromal ell recruitment factors. List the factors.

A

PDGF-A
PDGF-C
TGF-Beta = transforming growth factor

52
Q

What is the stroma?

A

This is a heterogeneous compartment comprising of fibroblastic, inflammatory and immune cells.

53
Q

What PDGF factor do endothelial cells produce?

A

Endothelial cells produce PDGF-B which promotes recruitment of pericytes in the microvasculature.

54
Q

Newly-forming capillaries synthesise a new basement membrane. During this process, what must be inhibited to permit the deposition and assembly of ECM components?

A

Extracellular proteolysis

55
Q

How are the newly formed capillaries stabilised?

A

Stabilisation requires the recruitment of pericytes and smooth muscle cells which is regulated by PDGF from the new capillaries.

56
Q

Note:

When sufficient vascularisation has occurred,

A

Angiogenic factors are downregulated and as a result the endothelial cells become quiescent = resting state.

57
Q

Note:

In pathological angiogenesis,

A

Signals that regulate the maturing of the vessels is also abnormal. So angiogenesis is not being switched off and the vasculature is not being properly insulated by pericytes and smooth muscle cells, leading to abnormal vasculatures and abnormally sized leaking vessels.

58
Q

What are the 5 classes of anti-angiogenic (antagonists) which are in clinical trials for the treatment of cancer?

A
  1. Inhibitors of proteases (inhibit synthesis of MMP)
  2. Inhibitors of endothelial migration and proliferation (VEGFR signaling)
  3. Inhibitors of angiogenic growth factors (VEGF, EGFR, HER2)
  4. Inhibitors of matrix proteins on the endothelial cell surface such as integrins
  5. Inhibitors with unique mechanisms (thalidomide and lenalidomide)
59
Q

What are two anti-VEGF therapies?

A
  1. Monoclonal antibodies directed against specific pro-angiogenic growth factors and their receptors.
  2. Small molecule tyrosine-kinase inhibitors (TKIs) of multiple pro-angiogenic growth factor receptors.
60
Q

How to tell difference between different drug names?

A

Monoclonal antibodies end with ‘mab’

Kinase inhibitors end with ‘nib’

61
Q

Describe what happens when VEGF binds to its receptor.

A

When soluble growth factor VEGF is released from cells which demand oxygen and nutrients, it binds to VEGF receptor on the surface of endothelial cells. Once it binds, receptor dimerises leading to autophosphorylation of the receptor, providing docking sites where there is intracellular signaling proteins and activation of the signaling cascades.
(Therapeutics developed interfere with the signaling pathway.)

62
Q

What is bevacizumab?

A

It is an anti-VEGF monoclonal antibody. It binds and neutralises all forms of VEGF and reduces free plasma VEGF levels to undetectable. Half life of 14-21 days.

63
Q

What is the side effects of bevacizumab?

A

Hypertension
Proteinuria
GI perforations and bleeding

64
Q

What is ramicurimab?

A

It is an anti-VEGF humanised monoclonal antibody - binds to the VEGF-2 receptor. Half life of 15 days.

65
Q

What are the side effects of ramicurimab?

A

High bp
Diarrhoea
Headache
Low sodium

66
Q

Describe Alfibercept.

A

Alfibercept is a fragment of an antibody. It is a protein comprised of segments from the extracellular domains of VEGFR1 and VEGFR2. It is fused to a constant region of IgG1. It function as a soluble decoy receptor, binds VEGF in blood and prevents receptor binding. Prevents receptor signaling.

67
Q

What do protein kinases do?

A

Protein kinases catalyse the transfer of gamma phosphate from nucleotide triphosphates (ATP) to one or more amino acid residues in a protein substrate side chain resulting in a conformational change affecting protein function.

68
Q

What are tyrosine kinase inhibitors called?

A

Receptor tyrosine kinases (RTKs) and Non-receptor tyrosine kinases (NRTKs)

69
Q

What are NRTKs?

A

A subgroup of tyrosine kinases, intracellular cytoplasmic proteins or anchored to a cell membrane.

70
Q

How many subfamilies of NRTKs are there?

A

9 subfamilies

71
Q

How are NRTKs activated?

A

Activation occurs through various interactions with other signaling proteins and conformational changes. This reveals binding site and substrate domain of protein.

72
Q

What is Raf serine/threonine kinase?

A

Raf is a multi-domain protein made up of a Ras-binding domain (RBD), a cysteine-rich domain (CRD), a linker region and a catalytic kinase domain (KinaseD)

73
Q

Describe the functional unit of Raf?

A

The functional unit of Raf is a dimer formed by the kinase domain of two Raf protomers.

74
Q

Describe the structure of Raf?

A

Raf is an enclosed structure where the catalytic site is not accessible to substrates or ATP. Upon activation which usually occurs when binding to another intracellular signaling protein such as Ras for Raf - results in conformational change that opens the catalytic domain revealing the ATP and substrate binding domain of the protein.

75
Q

Name a tyrosine kinase inhibitor (TKI) and what it is used for.

A

Imatinib

- for chronic myeloid leukemia

76
Q

What are RTKs?

A

These are membrane-permeable organic molecules that diffuse cross the membrane bilayer and target the TKD nucleotide binding site. They have allosteric or competitive modes of inhibitory action.

77
Q

What does Sorafenib do?

Nexavar is the brand

A

Sorafenib inhibits the ATP binding site of Raf and inhibits the receptor tyrosine kinase domain of all the receptor tyrosine kinases.
Sorafenib is a tyrosine kinase inhibitor.

78
Q

What cancer is sorafenib usually used to treat?

A

Hepatocellular cancer (HCC)/liver cancer

79
Q

What are two problems associated with sorafenib?

A
  1. primary resistance
  2. acquired resistance - ie as the cancer progresses, the potency of sorafenib becomes lower until the cancer is completely resistant.
80
Q

What is the recommended dose of sorafenib?

A

Daily dose of 800mg

81
Q

What is thalidomide and how does it work?

A

They are immunomodulatory drugs with that imide group (IMiD). It binds cereblon which is an ubiquitin ligase. It degrades a number of potential targets and inhibits pro-angiogenic targets.

82
Q

Describe the draw backs of anti-angiogenic therapies.

A
  1. Prolonged/excessive administration of the drugs reduces the microvascular density within the tumour - can also compromise the delivery of chemotherapy to the tumour.
  2. Angiogenesis is a complex process involving many growth factors - difficult to target all growth factors.
  3. Vasculature can be formed by other methods not just angiogenesis:
    - sprouting angiogenesis
    - intussusceptive angiogenesis
    - vessel co-option
    - vasculogenic mimicry
  4. Mechanism of resistance
83
Q

How can survival rates be boosted when using anti-angiogenic therapies for cancer?

A

Must be used in combination with chemotherapy to increase survival rates and reduce side effects.

84
Q

What is intussusceptive angiogenesis?

A

Vasculature of a vessel splits to form two new vessels.

85
Q

What is vessel co-option?

A

Growing tumours can develop through this. It is a non-angiogenic process in which tumour cells utilise the existing vasculature.

86
Q

What is vasculogenic mimicry?

A

Process where aggressive tumour cells growth vasculature without the presence of endothelial cells.

87
Q

Name the anti-VEGF therapies used to treat diabetic retinopathy and macular degeneration (mainly wet AMD).

A

Macugen - pegaptanib
Lucentis - ranibizumab
Avastin - bevacizumab
Alfibercept

88
Q

How are anti-VEGF therapies administered to treat ocular conditions?

A

Drugs injected into the vitreous humour - pass into the subretinal space, where vessels proliferate. The neovascularisation is then blocked - prevents leaky vessels bleeding into the retina.
Some drugs don’t require intravitreal injection.

89
Q

How does ranibizumab work in treating ocular conditions?

A

Ranibizumab is an antibody fragment

- these neutralise VEGF and prevent the VEGF from interacting with VEGF receptor

90
Q

What drug is under the brand name Macugen and how does it work?

A

Pegaptanib

- it is a VEGF antagonist

91
Q

What is the difference between aptamer and antibody?

A

Aptamers are oligonucleotide or peptide molecules that bind to a specific target molecule.
Aptamers are more stable that antibodies and have a longer shelf-life.
Aptamers are produced through a simple and inexpensive process and the time required to generate aptamers is comparatively short. Unlike antibodies, aptamers do not need animals or an immune response for their production.

92
Q

What is pro-angiogenic therapy used for?

A

Used to speed up wound healing.

93
Q

What is used for pro-angiogenic therapy?

A

Recombinant growth factor proteins.

PMY2106 Medicinal Substances (9 decks)

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