What is angiogenesis?
formation of new blood vessels
Where can angiogenesis occur?
small vessels where endothelium isnt so thick so sprouting can occur
Physiological vs pathological reasons for angiogenesis:
Physiological-menstrual cycle, wound healing, development
pathological-cancer/retinopathies
What is the initial stimuli for angiogenesis?
Hypoxia
Summarise angiogenesis:
Hypoxia
VEGF
Binds + activates and causes endothelial cell proliferation
Directional migration towards area they are needed
ECM remodelling
Tube + loop formation
Vascular stabilisation
How do endothelial cells directionally migrate towards the area they are needed?
Due to growth factor gradient
What is HIF?
Hypoxia induced transcription factor
What does HIF cause?
transcription of hypoxia inducible genes which stimulate angiogenesis
What controls levels of HIF?
pVHL
What type of gene is pVHL?
tumour suppressor gene
Apart from sprouting angiogenesis what other ways can new blood vessels be made?
vasculogenesis-in embryos
arteriogenesis-large blood vessels
What is angiogensis a balance between?
inhibitors + activators of angiogensis
Once new blood vessels have formed what needs to happen to them?
stabilisation
Summarise how sprouting angiogenesis occurs:
Tip cell chosen=navigation
cells below become stalk cells proliferate to push tip up
branching coordination
tip cell fusion + lumen forms
What does VEGF stand for?
vascular endothelium growth factor
What are the 5 VEGFs?
VEGF A, B, C, D
Placental growth factor (PIGF)
What are the 3 tyrosine kinase VEGF recepotrs?
VEGFR-1
VEGFR-2
VEGFR-3
What are the VEGF co-receptors?
Nrp1 + 2
Which receptor is the major mediator of VEGF dependent angiogenesis?
VEGFR-2
What does VEGF do exactly?
Hypoxia stimulates its release
It binds to VEGFR2 receptor on endothelial cell=this is now the tip cell
How do Tip cells communicate with stalk cells?
Notch pathway
Explain the Notch pathway:
Tip cell releases a ligand which binds to notch receptor on stalk cells
intracellular domain of notch receptor is cleaved–>nucleus of stalk cell
What helps endothelial cells migrate?
integrins
What supports sprouting?
myeloid cells
What carves tunnels so endothelial cells dont have to work as hard?
macriphages
Which kind of cells contain lots of angiogenesis regulators?
platelets
2 things important for stabilising blood vessels?
Tight junctions
Pericytes
What kind of protein interactions are tight junctions?
Homophillic-between same protein
2 reasons why tight junctions are important:
control cell permeability
Control contact inhibition
What does contact inhibition ensure?
Cells grow in single monolayer
What 2 things do pericytes do to stabilise vessels?
wrap around new vessels to stabilise them
Release ang 1
What are Ang 1 and ang 2 part of?
angiopoietin-tie 2 receptor system
What does Ang 1 vs Ang 2 do?
ang-1=stability
ang-1=promotes vascular instability
Pericytes can produce…….
ang 1 + 2
What is the difference between VEGF vs angiopoietin-Tie 2 receptor system?
VEGF=essential driver of angiogenesis
Angiopoietin-Tie 2 receptor system=modulator
What are pericytes also called?
mural cells
Why would targeting angiogenesis for cancer be a good idea?
tumours are highly vascularised
What is the angiogenic switch?
discrete step when tumours require their own blood supply
What triggers angiogenic switch?
tumour hypoxia
Compare small vs large tumours in terms of blood supply:
small tumours dont require own blood supply as they can get oxygen + nutrients by diffusion from nearby vessels
large tumours secrete angiogenic factors to stimulate angiogenesis
Differences between normal + tumour vasculature?
leaky
irregular shape
loose pericytes
breakages
Why is tumour vasculature different?
whole physiological package of angiogenic factors not released-only VEGF released
Why can this abnormal tumour vasculature be helpful for tumours?
increased intersitial pressure means drugs struggle to access tumour
2 cells that help tumour angiogenesis:
platelets
macrophages
3 examples of VEGF therapy:
Anti VEGF antibodies (Avastin)
VEGF receptor blockers
VEGF downstream signalling pathway blockers
Why is avastin not that good?
lots of side effects + limited efficacy
3 possible reasons tumours become resistant to VEGF inhibition:
vasculogenesis mimicry-cancer cells function like blood vessels
Tumour vessels not as sensitive to VEGF inhibition
Making tumour hypoxic causes it to release something else?
