Cancer 8: Angiogenesis Flashcards
What are the different types of disease angiogenesis?
Insufficient
- baldness
- MI (ischaemia) (Important)
- limb fractures
- thrombosis
Vascular malformations
- Angiodysplasia (HHT)
- Cerebral malformations
Excessive
- Retinal disease
- Cancers (important)
- Atherosclerosis
- Obesity
How are blood vessel made?
Vasculogenesis (bone marrow progenitor cell)
Angiogenesis (sprouting) - (important one to learn)
Arteriogenesis (collateral growth
Describe the process of sprouting angiogenesis
1) Lack of oxygen (hypoxia - promotes GF)
2) GF activates endothelial cells
3) endothelial cells undergo conformational change
4) sprout towards the GFs
5) Tip cells (the leader) tells other cells (stalk cells) to stay the same. while it sprouts out.
How is angiogenesis regulated?
It is regulated with a balance of inhibitors and activators
Inhibitors
- Thrombospondin-1
- Statins (angiostatin)
Activators
- VEGFs (vascular endothelial growth factor)
Give one trigger of angiogenesis
Hypoxia is a trigger for angiogenesis
HIF: hypoxia-inducible transcription factor, controls regulation of gene expression by oxygen. In the absence of oxygen it transcribes VEGF.
pVHL: Von Hippel Lindau tumour suppressor gene, controls the levels of HIF. In the presence of oxygen HIF is bound to pVHL which inhibits HIF.
What are the members of the VEGF family?
VEGF-A VEGF-B VEGF-C VEGF-D PlGF (placental growth factor)
What receptors to VEGF bind to?
Tyrosine kinase receptors:
VEGF receptor: Three types - VEGF receptor 1,2 and 3.
2 co-receptors: Nrp1 and Nrp2
Describe VEGFR-2
It is the major mediator of VEGF-dependent angiogenesis, activating signalling pathways that regulate endothelial cell migration, survival and proliferation.
What specialised cells are involved in sprouting angiogenesis?
In sprouting angiogenesis, specialised endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of VEGF.
The tip cell moves towards the VEGF gradient. Not every cell becomes a Tip cell this is controlled by notch signalling.
What is the canonical notch signalling pathway
Notch receptors and ligands are membrane-bound proteins that associate through their extracellular domains.
The intracellular domain of Notch (NICD) translocates to the nucleus and binds to the transcription factor RBP-J
The notch receptor would be on the stalk cell while the ligand is on the tip cell.
Describe selection of Tip cells: VEGF/Notch signalling
1) In stable blood vessels, Dll4 and Notch signaling maintain quiescence
2) VEGF activation increases expression of Dll4
3) Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell. One cell just decides to be the tip cell
4) Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype
5) Adjacent cells (Stalk cells) form the base of the emerging sprout, proliferate to support sprout elongation.
What happen during sprout outgrowth?
Stalk elongation
Tip guidance
stabilisation and quiescence
What is Ve-cadherin?
- Constitutively expressed at junctions
- Mediates adhesion between endothelial cells
- Controls contact inhibition of cell growth - promotes single layer of cells.
- Promotes survival of EC
What cells stabilise the neovessels?
Mural cells - pericytes produce the stabilzing factor angiopoietin-1
What is the angiopoietin-Tie2 pathway?
Ang-1 and Ang-2 are antagonistic ligands of the Tie2 receptor
Ang-1 binding to Tie2 promotes vessel stability and inhibits inflammatory gene expression
Ang-2 antagonises Ang-1 signalling, promotes vascular instability and VEGF-dependent angiogenesis
