Angiogenesis Flashcards
When can physiological angiogenesis occur?
- Embryonic development
- Menstrual cycle
- Wound healing
When can pathological angiogenesis occur?
• CANCER
- Chronic inflammatory diseases
- Retinopathies
- Ischaemic diseases
- Vascular malformations
What 3 things can angiogenesis be?
Insufficient
• e.g. baldness, MI
Involved in vascular malformations
• e.g. Angiodysplasia (HHT & VWD)
Excessive
• e.g. retinal disease, cancers, atherosclerosis
Angiogenesis is just one form of creating new blood vessels - what are some other ways?
VASCULOGENSIS
• using bone marrow progenitor cells
ARTERIOGENSIS
• collateral growth of vessels to accommodate occulusions
Basic model of sprouting angiogenesis?
- Selection of sprouting ECs
- Sprout outgrowth & guidance
- Sprout fusion & lumen formation
- Perfusion & maturation
What is a common trigger for angiogensis and explain what molecules help
Hypoxia
HIF
• Hypoxia-Inducible TF
• controls gene regulation
pVHL
• protein Van Hippel-Lindau TSG
• controls levels of HIF
Using the molecules invovled, describe angiogensis and hypoxia
Absence of O2
•pVHL does NOT bind to HIF
• HIF translocates to the nucleus –> binds to HIF-region
• induces translation of hypoxic factors
Presence of O2
• pVHL adds a hydroxyproline group to HIF
• HIF is therefore DEGRADED by a proteasome
VEGF and hypoxia?
One of the targets of HIF is VEGF (vascular endothelial GF)
Describe VEGF
5 families
• VEGF-A/B/C/D & Placental GF (PIGF)
3 TK-receptors
• VEGFR-1/2/3
AND
• co-receptors neuropilin (Nrp1, Nrp2)
VEGFRs can dimerise with other forms of VEGFRs
• i.e. VEGFR-2 –> VEGFR-3
Which VEGR is the major mediator of VEGF-dependant angiogenesis?
VEGFR-2
3 broad steps of the Angiogenetic Process?
(1) Tip Cells & Canonical Notch Signalling
(2) Sprout Outgrowth & Guidance
(3) Stabilisation & Quiescence
What happens in the 1st part of the Angiogentic Process (1) Tip Cells & Canonical Notch Signalling
Tip cells:
• Endothelial tip cells lead the outgrowth of blood-vessels towards gradients of VEGF
• Tip cell selection is based on “Notch Signalling” between the adjacent endothelial cells at the angiogenic front
Canonical Notch Signalling:
• Tip cells express NOTCH LIGANDS = binds to notch receptors on cells = signals division
• The intracellular domain of Notch (NICD) translocates to the nucleus and binds to the transcription factor RBP-J
Explain how Tip Cells are Selected for
Selection of Tip Cells:
- Stable – DII4 and Notch signalling maintain quiescence.
- Unstable – VEGF activation increases expression of DII4.
- DII4 drives Notch signalling in the adjacent cell which inhibits expression of VEGFR-2 (as they are stalk cells!).
- DII4-expressing Tip cells acquire a motile, invasive and sprouting phenotype.
- Stalk cells (adjacent cells) form the base of the sprout and proliferate to support the sprout elongation.
What happens in the 1st part of the Angiogentic Process (2) Sprout Outgrowth & Elongation
MYELOID CELLS are recruited to support and guide the sprout (stimulated by Ang-II)
Macrophages have a large role in angiogenesis anastomosis:
• Macrophages carve out tunnels in the ECM for subsequent capillary infiltration.
• Tissue-resident macrophages associate with the tip-cells during anastomosis to support the structure.
What is therefore the role of macrophages in the 2nd stage?
Stabilisers of new vessels
Explain what happens in the 3rd stage (3) Stabilisation & Quiescence
Barrier formation facilitates the stabilisation of the vessel - it is associated with:
• VE-Cadherins & Ang-I
Too much VEGF and there is too much sprouting and not enough stabilisation.
Broadly state what stabilisation involves
(1) Switching OFF angiogenesis
• too much VEGF not ideal!
(2) Endothelium reformation
(3) Recruiting neural cells (pericytes)
Explain (2) Endothelium Reformation
In order to form a monolayer (for the barrier), need to forn JUNCTIONS between cells
VE-Cadherins:
• constitutively expressed at junctions
• controls contact inhibition of cell growth.
• promotes the survival of the ECs.
Explain (3) Recruiting Neural Cells (pericytes)
Pericyte maturation facilitates the stabilisation of the vessel
• Mural cells = VSMCs and pericytes
Pericytes and mural cells use an Ang/Tie-2 system to stabilise the vessel.
Explain the Ang/Tie-2 system used by Pericytes & Mural cells to stabilise the cells
Angiopoietin-Tie 2 Lignad-Receptor System:
Ang-1 and Ang-2 ANTAGONISE the Tie-2 receptor:
Tie-2 is a receptor that can bind Ang-1
Ang-1 promotes vessel stability and inhibits inflammatory gene expression
Ang-2 antagonises Ang-1 signalling
• leads to vascular instability and VEGF-dependant angiogenesis.
• Ang-2 levels are increased in sepsis, CKD and congestive heart failure.
SO Ang-1 = GOOD
Ang-2 = BAD
What does the size of the tumour mean for its growth:
<1mm?
>1mm?
<1mm:
• receive oxygen and nutrients by diffusion from the host
> 1mm:
• require the “Angiogenic switch” so that the tumour can continue to grow
• this is done once the tumour starts to secrete angiogenic factors
• the “switch” occurs discretely AND at different steps in the tumour-progression pathway
What are the characteristics of the Tumour Blood Vessels?
Irregular shape
• Dilated, torturous
Not organised into arteries/veins/capillaries
Leaky (overproduction of VEGF)
Perivascular cells loosely associated.
May recruit endothelial progenitor
cells from bone marrow.
Therapeutic strategies targeting the VEGF Pathway?
Anti-VEGF Abs
• Avastin/Bevacizumab
Soluble VEGF Receptors
• VEGF-Trap
Anti-VEGFR Abs
• IMC-1121b
Small-molecule VEGFR Inhibitors
• Vatalanib, Sunitinib
Explain how Avastin/Bevacizumab are used?
ANTI-angiogenics
• via. Anti-VEGF Abs
Used in combination with other drugs to treat cancer:
• Cervical, colorectal, glioblastoma, NSCLC, ovarian
Avastin therapy has many side effects and a limited efficacy:
• This is as VEGF is not only essential for angiogenesis BUT also for HOMEOSTASIS OF ENDOTHELIUM
SEs: • GI perforation • hypertension • proteinuria • VTE • haemorrhage • wound healing complications
• No quality of life or survival advantage over chemo alone.
