Angiogenesis Flashcards
What is physioloical angiogenesis?
ESSENTIAL for embryonic development, wound healing and the menstrual cycle
What is vasculogenesis?
involves bone marrow progenitor cells (during development) that form blood vessels from scratch
What is angiogenesis?
Vessels sprout from a PRE-EXISTING blood vessel - most common in adults and involved in disease process
pro-angiogenic stimulus triggers the activation of specific selected endothelial cells -> conformational change
cytoskeleton changes polarity - allows it to sense the outside world (senses a stimulus that allows the direction of blood vessel formation)
At the same time, the cell communicates with other nearby endothelial cells, in order to instruct them to divide, to form vessels.
Cells begin to chew up the matrix, and eventually they fuse with a sprout coming from elsewhere
What is arteriogenesis?
collateral growth (mechanism through which collaterals are formed)
Collaterals may bypass a blockage
What features of the cytoskeleton of the tip of the endothelial cell allow it to for new vessels?
must be modified and it needs to control the interaction with neighbouring cells at cell-cell junctions.
- The tip cells will keep on moving until they find another tip cell, with which they will fuse
- tip cells themselves do not divide - require their neighbouring cells to divide behind them to push the tip cells towards the GF
- Eventually, the tip cell will meet another tip cell and it will fuse and stabilise
How is angiogenesis regulated
There are activators and inhibitors of angiogenesis - balance of these 2 groups regulates angiogenesis
There are some proteins/regulators that are absolutely essential e.g. VEGF – a loss of one allele of VEGF is incompatible with life.
How does hypoxia trigger angiogenesis?
HIF is a growth factor that controls regulation of gene expression by oxygen
- When oxygen is plentiful, HIF transcription factor is bound by a protein: pVHL – a tumour suppressor gene
- When bound to HIF, pVHL induces ubiquitination (inactivation by the addition of ubiquitin) and degrades HIF.
- THE MOMENT OXYGEN IS NOT PLENTIFUL, pVHL no longer binds to HIF -> HIF is not degraded and enters the nucleus to bind HIF-beta -> drives transcription of genes that promote angiogenesis, such as VEGF (vascular endothelial growth factor)
What are the different types of VGEF and VGEF receptors?
5 members of the VEGF family: - VEGF-A VEGF-B - VEGF-C - VEGF-D - PIGF (placental GF)
3 tyrosine kinase receptors for VEGF:
- VEGFR-1
- VEGFR-2
- VEGFR-3
2 co-receptors for VEGF:
- Neuropilin-1 (Nrp1)
- Neuropilin-2 (Nrp2
What is notch signalling?
pathway crucial for selection of tip cells - between adjacent endothelial cells at the angiogenic front
- In stable blood vessels, Dll4 and Notch signalling maintain quiescence.
- VEGF activation increases expression of Dll4.
- Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell.
- Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype.
- Adjacent cells (Stalk cells) form the base of the emerging sprout, and proliferate to support sprout elongation.
What happens when the notch ligand binds to the notch receptor?
activates it by cleaving the intracellular domain (NICD) -> NICD translocates to the nucleus where it binds to the TF RBP-J and regulates transcription
When a tip cell is chosen, it begins to express notch ligand which binds to the stalk cells’ notch receptors
- It tells them that ‘I am the tip cell, you are the stalk cells’
The stalk cells then begin to divide and push the tip cell towards the growth factor
- the notch ligand is also called Delta-like ligand 4 (Dll4)
How is sprout outgrown guided and stabilised?
cells will interact with the ECM and there will be guidance systems in place
Macrophages carve out tunnels in the ECM, providing avenues for subsequent capillary infiltration - appear to help stabilise newly formed vessels (by promoting tip cell fusion)
Once the tip cells have fused and the stalk cells are separating to form a patent tube, the new vessel needs to stabilise - involves reforming the endothelial monolayer barrier and recruiting neural cells (pericytes) and switching off the active angiogenesis process
*MYELOID CELLS IN THE RETINA CAN HELP THE PROCESS BY WRAPPING AROUND ENDOTHELIAL CELLS, TO STABILISE THE PROCESS
What does vascular endothelial (VE)- cadherin do?
- Constitutively expressed at junctions
- Mediates adhesion between endothelial cells (via homophillic interaction between cadherins)
- Controls contact inhibition of cell growth
- Promotes survival of EC
- essential for stabilisation and quiescence - loss of cadherin control is one of the hallmarks of some epithelial cancers
What do pericytes do?
Pericytes can wrap around the capillaries- produce a growth factor called ANGIOPOIETIN-1 (stabilising factor)
What are mural cells?
generally refers to smooth muscle cells and perictyes
What happens in the angiopoietin-Tie2 ligand-receptor system?
There are two ligands, which are ANTAGONISTIC: angiopoietin-1 (promotes stability, anti-inflammatory, homeostatic) and angiopoietin-2 (stored in endothelial cells, antagonises angiopoietin-1).
- Tie2 is a receptor that can bind to Angiopoietin 1
- Angiopoietin 1, when it binds to Tie2, promotes quiescence in the vasculature
- Angiopoietin 2 gets released when you need to form new blood vessels, when you need to respond to inflammation or when the vasculature needs to be destabilised
