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Intercal - Adaption in physiology > Angiogenesis > Flashcards

Angiogenesis Flashcards

1
Q

Define angiogenesis

A

The growth of new blood vessels from the existing vasculature.

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2
Q

How does angiogenesis happen

A

Caused by the migration and proliferation of endothelial cells

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3
Q

What is vasculogenesis

A

“the development of the vascular network from endothelial precursor cells, normally during embryogenesis

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4
Q

What is arteriogenesis

A

blood vessel maturation by recruitment of pericytes and smooth muscle cells increasing the number of cell layers

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5
Q

How is angiogenesis adaptive

A

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.

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6
Q

What processes increase the rate of angiogenesis

A

Exercise - aerobic (cardiac muscle) and anaerobic (skeletal muscle)
Pregnancy - placental growth
Ageing
Altitude
Weight loss/gain
Wound healing

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7
Q

Give some pathological conditions which decrease angiogenesis

A

Atherosclerosis
Preeclampsia
Chronic wounds
Alzheimers

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8
Q

Give some pathological conditions where angiogenesis is increased

A

Cancer
Macular degeneration - vessels grow over cornea
IBD - due to inflammation
MS - due to inflammation
Arthritis - inflammation
Asthma - inflammation

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9
Q

How is angiogenesis regulated in regards to physiological limit

A

Will grow to a physiological limit in health and retract when not needed.

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10
Q

Name the 6 stages of angiogenesis

A

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

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11
Q

How does stage 1 - the release of angiogenic growth factors work

A

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)

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12
Q

What stimulates the release of VEGF in stage 1 - angiogenic growth factor release

A

Hypoxia

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13
Q

How does hypoxia regulate VEGF

A

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.

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14
Q

How does oxygen act as a negative feedback method for VEGF

A

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

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15
Q

How does HIF-1 increase VEGF release

A

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.

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16
Q

How does stage 2 - growth factors activate endothelial cells work

A

VEGF binds to specific receptors (VEGFR-2) located on the endothelial cells of nearby pre-existing blood vessels. This activates them.

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17
Q

Give some features of VEGF2

A

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

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18
Q

How does stage 3 - proteolysis of the ECM work

A

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

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19
Q

How does stage 4 - Migration of proliferation of endothelial cells work

A

The endothelial cells begin to proliferate and migrate out through the dissolved holes of the existing vessel towards the hypoxic tissue.

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20
Q

How does stage 5 - Sprouting vessels and lumen formation work

A

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

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21
Q

How does stage 6 - vessel stabilization work

A

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.

22
Q

What cells initiate vasculogenesis

A

Results from bone marrow-derived endothelial progenitor cells (EPC) migrating and differentiating into endothelial cells

23
Q

What is vessel co-option

A

Tumour cells can co-opt pre-existing vessels, i.e. cancer cells move to find sufficient oxygen/nutrients

24
Q

What is vascular mimicry

A

Tumour cells can mimic endothelial cells nearby receiving sufficient oxygen and nutrients
Do this by putting out similar proteins and signals

25
Q

Give the basic stages of vasculogenesis

A

Haemopoietic stem cells –> haemangioblast –> endothelial progenitor cells –> vasculogenesis –> angio/arteriogenesis –> mature vasculature

26
Q

Why is vasculogenesis important

A

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.

27
Q

What happens in aortic stenosis regarding angiogenesis

A

Aortic valves should be avascular, however during thickening and calcification - monocytes and macrophage infiltration occur which drives neovascularization making the aortic valve vascular.

28
Q

What is the role of soluble VEGFR1 in human corneas

A

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

29
Q

What mammal doesn’t have soluble VEGFR1 and how does this animal present

A

Manatee - vascularised corneas

30
Q

What are the levels of soluble VEGFR1 over time in aortic stenosed valves

A

Decreases - resulting as an increase in vascularization

31
Q

The process of vessel retraction in angiogenesis

A

Cell apoptosis and then an inflammatory response of macrophages to sweep up the debris.

32
Q

Explain the process of recruiting smooth muscle cells in angiogenesis

EXTRA READING - livanainen 2003

A

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.

33
Q

What is the role of soluble HB-EGF in tumourgenesis

EXTRA READING - Ongusaha 2004

A

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

34
Q

Why is vascular mimicry considered vasculogensis and not angiogenesis

EXTRA READING - ANGARA 2017

A

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.

35
Q

What do VM vessels look like
EXTRA READING - ANGARA 2017

A

Matrix rich structures in laminin (basal lamina substance) in nest or lobule shaped closed loops.

36
Q

What tumours is VM found in
EXTRA READING - ANGARA 2017

A

Breast
Ovarian
Prostate
Lung
GBM

37
Q

How do tumour cells grow blood vessels

EXTRA READING - ANGARA 2017

A

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

38
Q

Why was vatalanib (the protein kinase inhibitor for VEGF) seen to make GBM grow more instead of shrink them

EXTRA READING - ANGARA 2017

A

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

39
Q

Why is there limited treatment vessel co-option

EXTRA READING - TEUWEN 2021

A

Poorly understood but discovered due to anti-angiogenic therapy resistance and a worse prognosis.

40
Q

What induced vessel co-option

EXTRA READING - TEUWEN 2021

A

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.

41
Q

What happens with age regarding angiogenesis

EXTRA READING - Olsen 2020

A

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,

42
Q

What causes angiogenesis during exercise

EXTRA READING - Wagner 2001

A

Exercise results in very low O2 levels in the muscle which the hypoxia stimulates VEGF

43
Q

What role does soluble VEGFR1 play in pregnancy hypertensive disorders

WIDER READING - Tripathi 2012

A

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

44
Q

How can sVEGF1 be used to monitor hypertensive disease in pregnancy

WIDER READING - Tripathi 2012

A

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.

45
Q

How is muscle blood supply affected in exercise

EXTRA READING - BLOOR 2005

A

Increases level of VEGF due to hypoxia

Increase in mRNA to make VEGFR1 and 2 to increase muscle responsiveness to VEGF

46
Q

What did angiogenesis of cardiac muscle show when exposed to exercise

EXTRA READING - BLOOR 2005

A

capillaries develop into small arterioles; thus capillary angiogenesis
potentially contributes to increased blood flow by providing a source of new arterioles.

47
Q

What is the role of VEGF-C

EXTRA READING - Carmeliet 2011

A

VEGF-C, a ligand of the VEGFR-2 and VEGFR-3 receptors, activates
blood-vessel tip cells - at new vessel formation

48
Q

What is the role of VEGFR-3

EXTRA READING - Carmeliet 2011

A

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

49
Q

What is the role of VEGFR3 in medicine

EXTRA READING - Carmeliet 2011

A

Can inhibit VEGFR2 dimerization or ligand binding through its antibodies which slows tumour progression so may have a role as an antiangiogenic candidate

50
Q

How are vascular smooth muscles cells recruited around new blood vessels

EXTRA READING - Carmeliet 2011

A

To stabilize endothelial cell channels, angiogenic endothelial cells release PDGF-B to chemoattract
PDGF receptor-β (PDGFR-beta) pericyte

51
Q

How are pericyte deficiency an issue for tumour cells

EXTRA READING - Carmeliet 2011

A

causes vessel leakage, tortuosity, microaneurysm formation and bleeding

Intercal - Adaption in physiology (11 decks)

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