Angiogenesis Flashcards
What are the three ways of making blood vessels?
- 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
What is the main signal for angiogenesis?
Hypoxia
What is the most important pro-angiogenic factor?
VEGF (Vascular Endothelial Growth Factor)
Explain the mechanism by which hypoxia triggers angiogenesis
- HIF (hypoxia-inducible factor) is a transcription factor that is responsible for the expression of genes involved in angiogenesis In normoxic conditions,
- Under normoxic conditions, HIF is bound to von Hippel Lindau protein (tumour suppressor), which induces ubiquitination (binding of ubiquitin which) inhibits HIF from promoting angiogenesis
- In hypoxic conditions, HIF is not bound to von Hippel Lindau (or ubiquitin) so it can regulate transcription and express genes involved in angiogenesis e.g. VEGF
How many members are there in the VEGF family? List them.
5 VEGF-A, B, C, D PIGF (placental growth factor)
How many tyrosine kinase receptors are there for VEGF? List them.
3 VEGFR 1, 2 and 3
How many coreceptors are there for VEGF? List them.
2 Neuropilin 1 (Nrp 1) and 2
Which receptor is the major mediator in VEGF-dependent angiogenesis?
VEGFR2
What pathway is crucial for the selection of tip cells?
Notch signalling
Outline the process of Notch signalling in endothelial cells, in regards angiogenesis
- The notch ligand (Delta-like ligand 4 or Dll4) on an endothelial tip cell binds the Notch receptor on an endothelial stalk cell. Note both the ligand and receptors have extracellular domains, and the receptor has an intracellular domain also
- The intracellular NICD domain is cleaved
- This then translocates to the nucleus and binds to the transcription factor RBP-J and regulates transcription essentially making the stalk cells grow while the tip cells are quiescent
- This sets up this ‘escalator-like’ growth for tip cells to spread before they meet and fuse
What is another name for the notch ligand?
Delta-like ligand (Dll4)
What effect does VEGF have on notch signalling and vice versa?
- 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
Describe the role that macrophages can play in angiogenesis
- Aid vessel anastomosis
- Macrophages help carve out the existing endothelia and basal lamina and tunnels through ECM at the site of sprouting - MMPs etc
- Help stabilise newly formed vessels by promoting tip cell fusion
Apart from macrophages, which other cell type is recruited to help with the stabilisation of the newly formed vessel?
- Pericytes
Which cell adhesion molecules are essential for vessel stabilisation and quiescence?
VE-Cadherin
What roles does cadherin play and where is it found in cells? Then mention a unique role that a form of cadherin plays in endothelial cells (also naming this form of cadherin)
- Cadherin is an essential part of the adhesive junctions between cells that allow them to form continuous monolayers
- Adjacent cadherins bind homophilically forming adjacent cell junctions, and this is important also in signalling
- Cadherin plays a role in contact inhibition of proliferation
- VE-cadherin is important in endothelial cell quiescence and stabilisation
What growth factor do pericytes produce that is important for stabilisation of new blood vessels?
Angiopoietin 1
Which important signalling pathway modulates the activation and return to quiescence of endothelial cells?
Angiopoietin-Tie2 signalling pathway
Describe the actions of angiopoietin 1
- Ang 1 promotes quiescence in the blood vessel
- Promotes stability
- Anti-inflammatory
Describe the actions of angiopoietin 2
- Ang 2 is an antagonist against the action of angiopoietin-1
- It gets released when you need to form a new vessel (promotes angiogenesis) and promotes vessel destabilisation
- It is also anti-inflammatory
What is the name given to the point at which a tumour begins to initiate angiogenic signals to generate new vasculature?
- Angiogenic switch
Describe what is meant by the angiogenic switch and when and why this occurs?
- This is when the tumour can no longer survive on diffusion from host vasculature and begins to become hypoxic and this makes it generate angiogenic signals in order to develop vasculature around it to support its greater metabolic requirements
What are some of the issues with tumour blood vessels?
- 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.
What is the aim of anti-angiogenic therapy in cancer?
- You want to prevent too much angiogenesis which would supply the tumour but you want to balance this with not reducing drug delivery too much in doing so or causing hypoxia
- Normalise tumour blood vessels to reduce hypoxia
- Improve efficiency of drug delivery
What are the consequences of being too aggressive with anti-angiogenic therapy?
- This can make the tumour blood supply inadequate for the delivery of drugs
What is avastin?
- Anti-VEGF humanised mouse antibody
- Also called bevacizumab
What are the side effects of avastin?
- GI perforation
- Hypertension
- Proteinuria
- Venous thrombosis
- Haemorrhage
What are the two main methods of unconventional resistance to VEGF blockade?
- 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
What did anti-VEGF therapy start getting used for other than cancer and how is it useful to treat this?
Start with the drug name that is used in this
- Lucentis
- Age-related macular degeneration (AMD)
- In AMD, there is abnormal growth of choroidal vessels which become leaky and thus oedematous, this oedema results in the visual impairment
What slightly modified form of avastin became licensed by the FDA to treat AMD?
Lucentis (ranibizumab)
Give 3 potential therapeutic uses for pro-angiogenic drugs
- Ischaemic diseases (e.g. MI, peripheral ischaemic disease) - neovascularisation to reduce ischaemia
- Vascular graft for coronary bypass surgery
- Vascular networks for organ regeneration
