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, 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
Which receptor is the major mediator in VEGF-dependent angiogenesis?
VEGFR2
What pathway is crucial for the selection of tip cells?
Notch signalling
What happens when the DLL4 ligand binds to the notch receptor?
The intracellular NICD domain is cleaved This then translocates to the nucleus and binds to the transcription factor RBP-J and regulates transcription
What is another name for the notch ligand?
Delta-like ligand (Dll4)
What effect does VEGF have on notch signalling?
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
Which cell type is involved in vessel anastomosis and helping stabilise newly formed vessels by promoting tip cell fusion?
Macrophages
Which other cell type is recruited to help with the stabilisation ofthe newly formed vessel?
Pericytes (mural cells)
Which cell adhesion molecules are essential for vessel stabilisation and quiescence?
VE-Cadherin
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
Describe the actions of angiopoietin 2.
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
What is the name given to the point at which a tumour begins to initiate signals to generate new vasculature?
Angiogenic switch- point at which tumours can no longer just rely on oxygen and nutrients from host vasculature so need a new vessel structure to supply them. Normally >1mm3
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?
To normalise tumour blood vessels to reduce hypoxia and 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
It’s the soluble part of a VEGFR that mops up VEGF
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 avastin start getting used for other than cancer?
Age-related macular degeneration (AMD)
Which cell leads angiogenesis
Tip
Which cell is notch ligand and receptor found on
Ligand- tip
Receptor- stalk
What maintains quiescence in stable blood vessels
Dll4 and notch signalling
Role of macrophages in angiogenesis
Carve out tunnels in ECM providing avenues for capillary infiltration
Which cell cell junctions exist in endothelial cells
Tight junctions
Adherens junctions
Features of endothelial cell junctions
Homophilic interaction mediates adhesion between the cells and intravellular signalling
Also survival
How do tumours achieve new vessel formation
They release angiogenic factors which initiates growth of sprouting capillary towards the tumour
Features of tumour blood vessels
Irregularly shaped, torted and dilated
Not clearly organised into capillaries, arterioles and venues
Leaky and haemorrhagic
Perivascualr cells loosely associated
Reason for leaky nature of tumour blood vessels
Overproduction of VEGF and loose association of pericytes
Effects of tumours on platelets
Aggregation, activation and degranulation
Overall outcome of platelet activation on tumours
Pro-angiogenic
Reason for leaky nature of tumour vessels
High VEGF
Alternative name for avastin
Bevacizumab
