Angiogenesis Flashcards
Define angiogenesis
The growth of new blood vessels from the existing vasculature.
How does angiogenesis happen
Caused by the migration and proliferation of endothelial cells
What is vasculogenesis
“the development of the vascular network from endothelial precursor cells, normally during embryogenesis
What is arteriogenesis
blood vessel maturation by recruitment of pericytes and smooth muscle cells increasing the number of cell layers
How is angiogenesis adaptive
Nerves - vessels form long cables parallel to neurons to ensure exchange.
Muscle - corkscrew vessels to maintain blood flow during contraction
Lung - wrap around alveolae to maximise gas exchange.
What processes increase the rate of angiogenesis
Exercise - aerobic (cardiac muscle) and anaerobic (skeletal muscle)
Pregnancy - placental growth
Ageing
Altitude
Weight loss/gain
Wound healing
Give some pathological conditions which decrease angiogenesis
Atherosclerosis
Preeclampsia
Chronic wounds
Alzheimers
Give some pathological conditions where angiogenesis is increased
Cancer
Macular degeneration - vessels grow over cornea
IBD - due to inflammation
MS - due to inflammation
Arthritis - inflammation
Asthma - inflammation
How is angiogenesis regulated in regards to physiological limit
Will grow to a physiological limit in health and retract when not needed.
Name the 6 stages of angiogenesis
Release of angiogenic growth factors
Growth factors activate endothelial cells
Proteolysis of ECM
Migration of proliferation of endothelial cells
Sprouting vessels and lumen formation
Vessel stabilization
How does stage 1 - the release of angiogenic growth factors work
Diseased or injured tissues produce and release angiogenic growth factors (proteins) that diffuse into the nearby tissues.
Most common growth factor is VEGF (VEGF-A)
What stimulates the release of VEGF in stage 1 - angiogenic growth factor release
Hypoxia
How does hypoxia regulate VEGF
upregulation of hypoxia-inducible factor-1a (HIF-1a)
HIF-1a is a transcription factor (i.e. it regulates gene expression when activated). In hypoxia, protein expression of HIF-1a is increased and its activation is also increased.
Oxygen acts as a negative feedback method.
How does oxygen act as a negative feedback method for VEGF
when oxygen is present, HIF-1a is hydroxylated and targeted for degradation by the von Hippel-Lindau protein. Hydroxylation is oxygen dependent and occurs at normal oxygen tension.
The reverse happens in hypoxia (HIF-1a isn’t hydroxylated) so HIF-1a alpha can stay around and bind with HIF1 beta to the promotor region (HRA - Hypoxia response element) of VEGF resulting in VEGF transcription and translation.
HIF 1a is constantly released and degraded
How does HIF-1 increase VEGF release
VEGF gene contains a hypoxia response element in its promoter, binding of activated HIF-1
activates gene expression of VEGF. Increased VEGF gene is translated into increased VEGF protein and is released from cells.
HIF-1a is increased.
No effect on HIF-1b levels.
How does stage 2 - growth factors activate endothelial cells work
VEGF binds to specific receptors (VEGFR-2) located on the endothelial cells of nearby pre-existing blood vessels. This activates them.
Give some features of VEGF2
Tyrosine kinase receptor family
autophosphorylates upon binding VEGF, leading to activation of multiple signalling cascades. This results in transcription factor activation, gene expression and protein expression. This leads to a change in endothelial cell phenotype to enable angiogenesis by making them more migratory and proliferative
How does stage 3 - proteolysis of the ECM work
The endothelial cell’s protein synthesising machinery begins to produce and release enzymes. These enzymes dissolve holes in the basement membrane surrounding the existing blood vessels. The basement membrane consists mostly of collagen and elastin.
These enzymes are called matrix metalloproteinases (MMPs) - they are activated by VEGF1 and HIF-1
These holes allow the endothelial cells to migrate through and sprout new vessels
How does stage 4 - Migration of proliferation of endothelial cells work
The endothelial cells begin to proliferate and migrate out through the dissolved holes of the existing vessel towards the hypoxic tissue.
How does stage 5 - Sprouting vessels and lumen formation work
Specialized adhesion molecules called integrins (isoforms avb3, avb5) serve as grappling hooks to pull the sprouting new blood vessel forward.
More MMP enzymes are used to dissolve the ECM in front of the sprouting vessel and the tissue remoulded around it.
Sprouting endothelial cells turn back around on themselves to form a blood vessel tube
How does stage 6 - vessel stabilization work
The blood tube reconnects with the pre-existing vessel to form vessel loops to circulate blood
Newly formed blood vessel tubes are stabilized by other cells (smooth muscle cells, pericytes) that provide structural support. Blood flow then begins.
What cells initiate vasculogenesis
Results from bone marrow-derived endothelial progenitor cells (EPC) migrating and differentiating into endothelial cells
What is vessel co-option
Tumour cells can co-opt pre-existing vessels, i.e. cancer cells move to find sufficient oxygen/nutrients
What is vascular mimicry
Tumour cells can mimic endothelial cells nearby receiving sufficient oxygen and nutrients
Do this by putting out similar proteins and signals
Give the basic stages of vasculogenesis
Haemopoietic stem cells –> haemangioblast –> endothelial progenitor cells –> vasculogenesis –> angio/arteriogenesis –> mature vasculature
Why is vasculogenesis important
Circulating endothelial progenitor cells are present in humans which if the correct signals are present - can form new blood vessels.
A lot of literature on this regarding repair of damaged tissue. Previously believed only angiogenesis was able to occur post-birth.
What happens in aortic stenosis regarding angiogenesis
Aortic valves should be avascular, however during thickening and calcification - monocytes and macrophage infiltration occur which drives neovascularization making the aortic valve vascular.
What is the role of soluble VEGFR1 in human corneas
It doesn’t activate intracellular signalling and acts as a VEGF sponge - this is because it doesn’t have a tyrosine kinase attached intracellularly therefore it binds to VEGF to prevent it binding to the membrane VEGFR and therefore prevent angiogenesis.
This shows that even cornea cells produce VEGF
What mammal doesn’t have soluble VEGFR1 and how does this animal present
Manatee - vascularised corneas
What are the levels of soluble VEGFR1 over time in aortic stenosed valves
Decreases - resulting as an increase in vascularization
The process of vessel retraction in angiogenesis
Cell apoptosis and then an inflammatory response of macrophages to sweep up the debris.
Explain the process of recruiting smooth muscle cells in angiogenesis
EXTRA READING - livanainen 2003
Endothelial-derived heparin binding EGF-like growth factor (HB-EGF) was shown to mediate this process by signaling via ErbB1 and ErbB2 receptors in SMCs to recruit them.
What is the role of soluble HB-EGF in tumourgenesis
EXTRA READING - Ongusaha 2004
Raised SHB-EGF in vivo - bladder in humans resulted in an increase in growth rate, colony-forming ability, and activation of cyclin D1 promoter,
as well as induction of vascular endothelial growth factor and MMPs
Why is vascular mimicry considered vasculogensis and not angiogenesis
EXTRA READING - ANGARA 2017
The process of VM is caused by tumour cells assuming an endothelial-like phenotype with no help from pre-existing host endothelial cells suggesting the process is vasculogenic in nature.
What do VM vessels look like
EXTRA READING - ANGARA 2017
Matrix rich structures in laminin (basal lamina substance) in nest or lobule shaped closed loops.
What tumours is VM found in
EXTRA READING - ANGARA 2017
Breast
Ovarian
Prostate
Lung
GBM
How do tumour cells grow blood vessels
EXTRA READING - ANGARA 2017
In early stages, angiopoietin-2 is released which triggers the promotion of endothelial activation, destabilization, and inflammation. Overtime, the tumour grows and angiopoietin-2 increases resulting in a loss of endothelial integrity which causes tumour hypoxia and therefore the recruitment of VEGF and therefore start the formation of vessels
Why was vatalanib (the protein kinase inhibitor for VEGF) seen to make GBM grow more instead of shrink them
EXTRA READING - ANGARA 2017
Seen that the loops formed in tumour angiogenesis increased when exposed to vatalanib because the vessels undergo VM in response to hypoxia induced by vatalanib.
Making GBM a lethal and resistant disease in regards to biologic treatment
Why is there limited treatment vessel co-option
EXTRA READING - TEUWEN 2021
Poorly understood but discovered due to anti-angiogenic therapy resistance and a worse prognosis.
What induced vessel co-option
EXTRA READING - TEUWEN 2021
showed a predominant enrichment in matrix-remodeling macrophages. Based on their expression signature of genes involved in matrix degradation and deposition, we speculate that this macrophage subtype might be able to assist invasive cancer cells to co-opt healthy lung vessels. For co-opting cancer cells to travel alongside pre-existing blood vessels, they must make their way through the interstitial stroma, which is dense in ECM. Matrix-remodeling macrophages might assist co-opting cancer cells by paving the way through matrix reorganization, involving degradation of the existing matrix (facilitating invasion by cancer cells) and deposition of the new matrix (anchor points for invading cancer cells). This hypothesis is further supported by our findings that these macrophages were located at the invasive forefront of co-opting metastases, where blood vessels become co-opted by cancer cells.
What happens with age regarding angiogenesis
EXTRA READING - Olsen 2020
Old women underwent an 8 week cardiointensive programme to determine if their low levels of VEFG in their myocytes and low VEGF release could be increased - did not significantly increase therefore - the findings indicate that aged women have a reduced potential for capillary growth in skeletal muscle which, with ageing,
What causes angiogenesis during exercise
EXTRA READING - Wagner 2001
Exercise results in very low O2 levels in the muscle which the hypoxia stimulates VEGF
What role does soluble VEGFR1 play in pregnancy hypertensive disorders
WIDER READING - Tripathi 2012
VEGF is needed during placental development. High levels of solube VEGFR1 were seen in pre-eclampsia.
Study was done to look at the levels of SVEGFR1 in mothers per week of gestation to determine if theres a link and if this canbe monitored for rationalising management plans.
Placenta showed very high levels of sVEGFR-1. This suggests that sVEGFR1 is restricting VEGF from doing its role and resulting in a dysregulation of angiogenesis and hypertension
How can sVEGF1 be used to monitor hypertensive disease in pregnancy
WIDER READING - Tripathi 2012
revealed the significant upregulation of sVEGFR-1 levels as the severity of disease increases from GH to eclampsia (both early- and late-onset of the disease) as compared with gestationally matched controls. Hence, sVEGFR-1 is a reliable tool to discriminate between different types of pregnancy-related hypertensive disorders.
How is muscle blood supply affected in exercise
EXTRA READING - BLOOR 2005
Increases level of VEGF due to hypoxia
Increase in mRNA to make VEGFR1 and 2 to increase muscle responsiveness to VEGF
What did angiogenesis of cardiac muscle show when exposed to exercise
EXTRA READING - BLOOR 2005
capillaries develop into small arterioles; thus capillary angiogenesis
potentially contributes to increased blood flow by providing a source of new arterioles.
What is the role of VEGF-C
EXTRA READING - Carmeliet 2011
VEGF-C, a ligand of the VEGFR-2 and VEGFR-3 receptors, activates
blood-vessel tip cells - at new vessel formation
What is the role of VEGFR-3
EXTRA READING - Carmeliet 2011
VEGFR-3 is necessary for the formation of the
blood vasculature during early embryogenesis, but later becomes a key
regulator of lymphangiogenesis — the formation of new lymphatic
vessels from pre-existing ones
What is the role of VEGFR3 in medicine
EXTRA READING - Carmeliet 2011
Can inhibit VEGFR2 dimerization or ligand binding through its antibodies which slows tumour progression so may have a role as an antiangiogenic candidate
How are vascular smooth muscles cells recruited around new blood vessels
EXTRA READING - Carmeliet 2011
To stabilize endothelial cell channels, angiogenic endothelial cells release PDGF-B to chemoattract
PDGF receptor-β (PDGFR-beta) pericyte
How are pericyte deficiency an issue for tumour cells
EXTRA READING - Carmeliet 2011
causes vessel leakage, tortuosity, microaneurysm formation and bleeding
