Angiogenesis

Question 1

What is angiogenesis?

Answer 1

New blood vessel growth.

Question 2

What physiological roles does angiogenesis have in health?

Answer 2

Embryonic development
Wound healing
Menstrual cycle

Question 3

What conditions are dependent on insufficient angiogenesis?

Answer 3

Baldness
MI- ischaemia
Limb fractures
Thrombosis

Question 4

What conditions are dependent on vascular malformations?

Answer 4

Angiodysplasia
HHT and VWD
Cerebral malformations
AVM/CCM

Question 5

What conditions are dependent on excessive angiogenesis?

Answer 5

Retinal disease
Cancers
Atherosclerosis
Obesity

Question 6

What are the 3 types of blood vessel formation?

Answer 6

Vasculogenesis (bone marrow progenitor cell)
Angiogenesis (sprouting)
Arteriogenesis (collateral growth)

Question 7

How is angiogenesis regulated?

Answer 7

Balance between inhibitors and activators.

Question 8

What are the inhibitors of angiogenesis?

Answer 8

Thrombospondin-1
Angiostatin
Endostatin
Canstatin
Tumstatin

Question 9

What are the activators of angiogenesis?

Answer 9

VEGFs
FGFs
PDGFB
EGF
LPA

Question 10

What is a key trigger of angiogenesis?

Answer 10

Hypoxia

Question 11

What is HIF?

Answer 11

Hypoxia-inducible transcription factor.

Controls regulation of gene expression by oxygen.

Question 12

What is pVHL?

Answer 12

Von Hippel-Lindau tumour suppressor gene.

Controls levels of HIF.

Question 13

What is VEGF?

Answer 13

Vascular endothelial growth factor.

Family of 5 members: VEGF-(A-D), placental growth factor (PlGF).

Question 14

What are the 3 tyrosine kinase receptors of VEGF?

Answer 14

VEGFR-(1-3)

Question 15

What is the major mediator of VEGF-dependent angiogenesis?

Answer 15

VEGFR-2

Activates signalling pathways that regulate endothelial cell migration, survival, proliferation.

Question 16

What is tip cell selection based on?

Answer 16

Notch signalling between adjacent endothelial cells at the angiogenic front.

Question 17

What are tip cells?

Answer 17

In sprouting angiogenesis, specialised endothelial tip cells lead the outgrowth of blood vessel sprouts towards gradients of VEGF.

Question 18

What are Notch receptors and ligands?

Answer 18

Membrane-bound proteins that associate through their extracellular domains.

Question 19

What does the intracellular domain of Notch (NICD) do in the canonical Notch signalling pathway?

Answer 19

Translocates to the nucleus and binds to the transcription factor RBP-J.

Question 20

What maintains quiescence in stable blood vessels?

Answer 20

DII4 and Notch signalling.

Question 21

What increases expression of DII4?

Answer 21

VEGF activation

Question 22

What dose DII4 drive?

Answer 22

Notch signalling

Question 23

What does Notch signalling inhibit?

Answer 23

Expression of VEGFR-2 in the adjacent cell

Question 24

In VEGF/Notch signalling, what are the qualities of the phenotype acquired by DII4-expressing tip cells?

Answer 24

DII4-expressing tip cells acquire a motile, invasive and sprouting phenotype.

Question 25

What is the role of stalk cells in VEGF/Notch signalling?

Answer 25

Adjacent cells (stalk cells) form the base of the emerging sprout, proliferate to support sprout elongation.

Question 26

What are the roles of VE-cadherin in angiogenesis?

Answer 26

Constitutively expressed at junctions Mediates adhesion between endothelial cells Controls contact inhibition of cell growth Promotes survival of EC

Question 27

What is the role of mural cells in angiogenesis?

Answer 27

Help to stabilise neovessels.

Question 28

What is the role of pericytes in angiogenesis?

Answer 28

Produce the stabilising factor, angiopoietin-1.

Question 29

What diseases are Ang-2 plasma levels raised in?

Answer 29

Congestive heart failure Sepsis Chronic kidney disease

Question 30

What does Ang-1 binding to Tie2 result in?

Answer 30

Promotion of vessel stability | Inhibition of inflammatory gene expression

Question 31

What are Ang-1 and Ang-2 in relation to Tie2?

Answer 31

Antagonistic ligands of the Tie2 receptor.

Question 32

What is the role of Ang-2 in angiogenesis?

Answer 32

Antagonises Ang-1 signalling | Promotes vascular instability and VEGF-dependent angiogenesis

Question 33

What is the angiogenic switch?

Answer 33

Discrete step in tumour development that can occur at different stages in the tumour progression pathway, depending on the nature of the tumour and its microenvironment.

Question 34

How do tumours smaller than 1mm^3 receive oxygen and nutrients?

Answer 34

Diffusion from host vasculature.

Question 35

What are the properties of tumour blood vessels?

Answer 35

Irregularly shaped, dilated, tortuous Not organised into definitive venues, arterioles and capillaries Leaky and haemorrhagic, partly due to excessive VEGF Perivascular cells are often loosely associated Some tumours may recruit endothelial progenitor cells from the bone marrow

Question 36

How do larger tumours (>1mm^3) receive oxygen and nutrients?

Answer 36

Require new vessel network. Tumour secretes angiogenic factors that stimulate migration, proliferation, and neovlessel formation by endothelial cells in adjacent established vessels. Newly vascularised tumour no longer relies solely on diffusion from host vasculature, facilitating progressive growth.

Question 37

What are the side effects of Avastin?

Answer 37

``` GI perforation Hypertension Proteinuria Venous thrombosis Haemorrhage Wound healing complications ```

Question 38

What was the first anti-angiogenic clinically proven to extend survival in cancer?

Answer 38

Anti-VEGF humanised mAb, Avastin.

Question 39

What is the efficacy of Avastin therapy for cancer?

Answer 39

Limited efficacy. No overall survival advantage over chemotherapy alone. No quality of life or survival advantage.

Question 40

What are the 2 modes of unconventional resistance to anti-angiogenic therapy in cancer?

Answer 40

Evasive resistance- an adaptation to circumvent the specific angiogenic blockade. Intrinsic or pre-existing indifference.

Question 41

What is vasculogenic mimicry?

Answer 41

Cancer cells form blood-carrying channels to supplement traditional angiogenesis in supplying nutrients to tumours. Plasticity of aggressive cancer cells forming de novo vascular networks. Associated with malignant phenotype and poor clinical outcome.

Question 42

What is age-related macular degeneration (AMD)?

Answer 42

Abnormal growth of choroidal blood vessels 'Leaky' vessels cause oedema Visual impairment

Question 43

What can anti-angiogenic therapies be used for (other than cancer)?

Answer 43

Abnormal retina vascularisation (diabetic retinopathy, wet AMD).

Question 44

What can pro-angiogenic therapies be used for?

Answer 44

Ischaemic disease (myocardial infarction, peripheral ischaemic disease)- promote neovascularisation to prevent ischaemic damage.

Question 45

What is the 'tumour-on-a-chip' platform?

Answer 45

Microphysiological system that incorporates human cells in a 3D ECM, supported by perfused human micro vessels. In vitro disease models incorporating tumour cells and vasculature may improve tumour modelling and drug screening.