Angiogenesis Flashcards
What is the physiology of angiogenesis
Development
Menstrual Cycle
Wound Healing
What is the pathology of angiogenesis
Cancer Chronic inflammatory diseases Retinopathies Ischemic diseases Vascular malformations
Give examples of growth factors that are involved in activating angiogenesis
VEGF family (vascular endothelial growth factor)
FGF family
TGF beta
PDGF
Give examples of extracellular matrix factors that inhibit angiogenesis
Thrombospondin-1
Angiostatin
Endostatin
Which surface receptors are involved in the regulation of angiogenesis
avb3
What are the 3 main ways of making blood vessels
- Vasculogenesis - mobilisation of endothelial progenitor cells (from the bone marrow)
- Angiogenesis - sprouting of new vessels (capillaries) from existing ones
- Arteriogenesis - collateral growth
Describe the process of sprouting angiogenesis
- Tip/stalk cell selection
- Tip cell navigation and stalk cell proliferation
- Branching coordination
- Stalk elongation, tip cell fusion, and lumen formation
- Perfusion and vessel maturation.
Which factor activates angiogenesis in response to hypoxia
HIF: hypoxia-inducible transcription factor
Controls regulation of gene expression by oxygen
When there is plenty of oxygen, HIF is rapidly degraded. Hypoxia - proteolytic mechanisms to slow, allowing HIF to act in the nucleus. HIF increases transcription of VEGF and some other cytokines.
What factor regulates angiogenesis in response to hypoxia
pVHL: Von Hippel–Lindau tumor suppressor gene
Controls levels of HIF (binds to HIF-alpha -> destruction)
What are the 5 members of the VEGF family
VEGF-A VEGF-B VEGF-C VEGF-D placental growth factor (PlGF)
What are the 3 tyrosine kinase receptors of VEGF
VEGFR-1
VEGFR-2
VEGFR-3
and co-receptors neuropilin (Nrp1 and Nrp2)
Which tyrosine kinase is the major mediator of VEGF-dependent angiogenesis
VEGFR-2
activates signalling pathways that regulate endothelial cell migration, survival, proliferation.
How is the tip cell selected and what does it do
The cell which receives the highest concentration of VEGF tells the adjacent cells that it alone will become the tip cell (via the Notch pathway)
Specialised tip cells lead the outgrowth of blood vessel sprouts up the VEGF gradient (towards hypoxia)
What are notch receptors and ligands
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
Explain the process of tip cell selection
- 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, proliferate to support sprout elongation.
What is the role of macrophages in angiogenesis
Participate in vessel anastomosis
Macrophages carve out tunnels in the extra cellular matrix (ECM), providing avenues for capillary infiltration
Tissue-resident macrophages can be associated with angiogenic tip cells during anastomosis
What is the role of platelets in angiogenesis
Link between cancer progression and thrombocytosis
Activated platelets are a source of VEGFA, PDGFs and FGF2
Tumours cause platelet activation, aggregation and degranulation
Explain the angiopoietin-Tie2 ligand-receptor system
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
How do tumours smaller than 1mm3 receive oxygen
Receives enough oxygen and nutrients by diffusion from existing vasculature
How do tumours bigger than 1mm3 receive oxygen
Require new blood vessels to continue growing
Tumor secretes angiogenic factors that stimulate migration, proliferation, and neovessel formation by endothelial cells in adjacent established vessels.
Newly vascularized tumor no longer relies solely on diffusion from host vasculature, facilitating progressive growth.
What is the angiogenic switch
A 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
Describe how tumour blood vessels are architecturally different to normal vessels
Irregularly shaped, dilated, and twisted
Not organised into definitive arterioles, capillaries, and venules
Leaky and haemorrhagic, with Perivascular cells more loosely associated
What are the potential approaches to compromising tumour vasculature
- inhibiting ECM breakdown, signal transduction or endothelial cell function (e.g. proliferation, migration, tube formation)
- blocking activators of angiogenesis
- antagonising receptors
- damaging the existing tumour vasculature
Give an example of an endogenous inhibitor of angiogenesis
Endostatin
Giving additional endostatin to cancer patients can significantly reduce the rate of growth of cancer
Give an example of a drug used in cancer treatment that involves inhibition of angiogenesis
Bevacizumab is a humanised anti-VEGF mAb
Avastin is its trade name.
Used as part of a combination of therapies
Explain the need for balance in inhibiting angiogenesis with drugs
Just eliminating pro-angiogenic molecules causes inadequate vasculature, and chemotherapy drugs cannot reach the tumour to kill it
Enough anti-angiogenic compounds are given to balance the surplus of pro- angiogenic ones
What are the side effects of bevacisumab/avastin
- GI perforation
- hypertension
- proteinuria
- venous thrombosis
- haemorrhage
- wound healing complications
Other than cancer treatment, what else can Bevacizumab/avastin be used for
Successful in stopping retinal vascularisation in macular degeneration
Coronary artery disease (use of a catheter to penetrate the blockage)
