Angiogenesis

Question 1

What are the three ways of making blood vessels?

Answer 1

Vasculogenesis – formation of new blood vessels from bone marrow progenitor cells

Angiogensis – formation of new blood vessels by sprouting from pre-existing vessels

Arteriogenesis – collateral growth of blood vessels that is dependent on shear stress and external factors like macrophages

Question 2

What is the main signal for angiogenesis?

Answer 2

Hypoxia

Question 3

What is the most important pro-angiogenic factor?

Answer 3

VEGF (Vascular Endothelial Growth Factor)

Question 4

Explain the mechanism by which hypoxia triggers angiogenesis.

Answer 4

HIF (hypoxia-inducible factor) is a transcription factor that is responsible for the expression of genes involved in angiogenesis
In normoxic conditions, HIF is bound to von Hippel Lindau protein (tumour suppressor), which inhibits HIF from promoting angiogenesis
In hypoxic conditions, HIF is not bound to von Hippel Lindau so it can regulate transcription and express genes involved in angiogenesis

Question 5

How many members are there in the VEGF family? List them.

Answer 5

VEGF-A, B, C, D

PIGF (placental growth factor)

Question 6

How many tyrosine kinase receptors are there for VEGF? List them.

Answer 6

3

VEGFR 1, 2 and 3

Question 7

How many coreceptors are there for VEGF? List them.

Answer 7

2 
Neuropilin 1 (Nrp 1) and 2

Question 8

Which receptor is the major mediator in VEGF-dependent angiogenesis?

Answer 8

VEGFR2

Question 9

What pathway is crucial for the selection of tip cells?

Answer 9

Notch signalling

Question 10

What happens when the notch ligand binds to the notch receptor?

Answer 10

The intracellular NICD domain is cleaved This then translocates to the nucleus and binds to the transcription factor RBP-J and regulates transcription

Question 11

What is another name for the notch ligand?

Answer 11

Delta-like ligand (Dll4)

Question 12

What effect does VEGF have on notch signalling?

Answer 12

It increases expression of Dll4
Dll4 then drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell
Dll4 expressing tip cells develop a motile, invasive and sprouting phenotype
Adjacent stalk cells form the base of the emerging sprout and proliferate to support sprout elongation

Question 13

Which cell type is involved in vessel anastomosis and helping stabilise newly formed vessels by promoting tip cell fusion?

Answer 13

Macrophages

Question 14

Which other cell type is recruited to help with the stabilisation of the newly formed vessel?

Answer 14

Pericytes

Question 15

Which cell adhesion molecules are essential for vessel stabilisation and quiescence?

Answer 15

VE-Cadherin

Question 16

What growth factor do pericytes produce that is important for stabilisation of new blood vessels?

Answer 16

Angiopoietin 1

Question 17

Which important signalling pathway modulates the activation and return to quiescence of endothelial cells?

Answer 17

Angiopoietin-Tie2 signalling pathway

Question 18

Describe the actions of angiopoietin 1.

Answer 18

Ang 1 promotes quiescence in the blood vessel

Question 19

Describe the actions of angiopoietin 2.

Answer 19

Ang 2 is an antagonist and gets released when you need to form a new vessel or when you need to respond to inflammation/vasculature needs to be destabilised

Question 20

What is the name given to the point at which a tumour begins to initiate signals to generate new vasculature?

Answer 20

Angiogenic switch

Question 21

What are some of the issues with tumour blood vessels?

Answer 21

They are not properly formed because the signals are not physiological
Vessels can be irregularly shaped, distended, tortuous
Leaky and haemorrhagic etc
Haemorrhage is common in tumours.

Question 22

What is the aim of anti-angiogenic therapy in cancer?

Answer 22

To normalise tumour blood vessels to reduce hypoxia and improveefficiency of drug delivery

Question 23

What are the consequences of being too aggressive with anti-angiogenic therapy?

Answer 23

This can make the tumour blood supply inadequate for the delivery of drugs

Question 24

What is avastin?

Answer 24

Anti-VEGF humanised mouse antibody

Also called bevacizumab

Question 25

What are the side effects of avastin?

Answer 25

GI perforation 
Hypertension 
Proteinuria 
Venous thrombosis 
Haemorrhage

Question 26

What are the two main methods of unconventional resistance to VEGF blockade?

Answer 26

Tumour adopts evasive strategy – adapts to bypass the angiogenic blockade
Intrinsic or pre-existing difference – a tumour may not have been particularly sensitive to VEGF in the first place

Question 27

What did avastin start getting used for other than cancer?

Answer 27

Age-related macular degeneration (AMD)

Question 28

What slightly modified form of avastin became licensed by the FDA to treat AMD?

Answer 28

Lucentis (ranibizumab)

Question 29

What are angiogenesis activators being used to try and treat?

Answer 29

Ischaemic disease - E.G. Used distally to occlusion in Ischaemic heart diseases.

Problem is trying to achieve balance of molecules to promote HEALTHY, BALANCED vessels.