angiogenesis

Question 1

summary of angiogenesis- type of vessel, growth factor, and main cause of angiogenesis

Answer 1

occurs in SMALL vessels, where VEGF (growth factor) bind to receptor on endothelium, usually due to hypoxia, triggering a cascade

Question 2

why angiogenesis good

Answer 2

for development, menstrual cycle and during wound healing

Question 3

why angiogenesis bad- name disease

Answer 3

occurs in cancer, inflammatory diseases, retinopathy etc

Question 4

how to produce blood vessels

Answer 4

not ONLY angiogenesis (sprouting), there is vasculogenesis (occurs in bone marrow) and arteriogenesis (when artery blocked)

Question 5

regulating angiogenesis- pro, anti, and stabilising

Answer 5

there are pro and anti-angiogenic factors, some of which are crucial (VEGF), some which we can survive without (VWF) there are also molecules that stabilise the blood vessel once its built

Question 6

what occurs upon normal O2 and hypoxia

Answer 6

HIF-alpha binds to pVHL when oxygen present- inhibits it when oxygen absent, it unbinds, and HIF-alpha goes into DNA and turns on genes that produce growth factors eg VGEF

Question 7

VGEF- types and receptors, with main receptor

Answer 7

5 kinds of VEGF, 3 tyrosine kinase receptors, with VEGFR2 being the main receptor for angiogenesis

Question 8

beginning of angiogenesis- VEGF, tip and stalk cells

Answer 8

VEGF eg produced by macrophages hits receptor and forms tip cell these tip cells lead sprouting of the vessel, and recruit other cells beneath (STALK cells) to grow as well

Question 9

Notch pathway- how tip cells recruit stalk cells, ligand involved

Answer 9

pathway involved between tip cell and stalk cell receptor has domain on CSF, and intracellular domain- when ligand binds to notch receptor on CSM of stalk cell, intracellular domain detaches and goes into nucleus to act as T.F ligand is DII4, which is upregulated when VEGF binds to tip cell

Question 10

next stage of angiogenesis- growing of sprout: role of integrins and macrophages, then fusion

Answer 10

vessel sprouting elongation occurs so that it migrates to tissue- integrins help with this migration macrophages also important- produce tunnels for sprouting vessels to direct them- also support tip cells during ANASTOMOSIS two adjacent tip cells then fuse to form a lumen

Question 11

role of platelets in angiogenesis

Answer 11

very important- have both pro and anti-angiogenic factors

Question 12

final stage- stabilisation of vessel: interaction and importance of junctions

Answer 12

vessels stabilised by forming junctions between them- done by homophilic interaction between endothelial cells (same transmembrane protein on each endothelial cell) allows control for influx of molecules eg inflammatory cells, and also control CONTACT INHIBITION of cells (how much endothelial cells grow)

Question 13

what else stabilises these new vessels

Answer 13

pericytes/mural cells, which produce substance part of the ANGIOPOIETIN TIE 2 system

Question 14

angiopoietin tie 2 ligand system - the ligands produce and effects

Answer 14

pericytes produce Ang 1 and 2, which are ANTAGONISTIC ANG 1 binds to Tie 2 receptor= vessel STABILITY ANG2 binds and does opposite: leads to vessel INSTABILITY= angiogenesis

Question 15

overall difference between Angiopoetin Tie 2 pathway and VEGF pathway

Answer 15

system is modulatory, but VEGF pathway is activatory

Question 16

clinical importance of Ang 2

Answer 16

raised in heart failure, sepsis and CKD, as very destabilising

Question 17

tumour angiogenesis with number

Answer 17

small tumours (below 1mm) can survive without ANY vessels, simply surrounding environment, but larger ones need them, so they produce certain angiogenic factors eg VEGF to form vessels

Question 18

what is it angiogenic switch

Answer 18

point at with tumour requires vessels, and can no longer survive with just simple diffusion

Question 19

features of tumour blood vessles

Answer 19

irregular shape, very tortuous, leaky, can have occlusion, and not organised into venules, arterioles, capillaries etc thus different from normal vessels

Question 20

molecules involved in tumour angiogenesis

Answer 20

fibroblasts which are pro-angiogenic pericytes are LOOSELY associated with these vessels= vessels leaky= haemorrhages platelets release pro-angiogenic factors- unknown whether blocking platelets will affect tumours

Question 21

main way of inhibiting tumour angiogenesis with main drug

Answer 21

inhibiting effects of VEGF eg anti-VEGF antibodies, receptor blockers reduce tumour growth avastin is the main drug- an anti-VEGF antibody

Question 22

problems with Avastin

Answer 22

has shown no survival advantage compared to ONLY chemotherapy mostly temporary benefit- tumour resists and grows again

Question 23

side effects of avastin

Answer 23

hypertension, GI perforation, problems with wound healing, proteinuria

Question 24

reasons why tumours resistant to anti-VEGF therapy

Answer 24

tumour responds to hypoxia by producing other angiogenic factors tumour vessels different- endothelium less sensitive to VEGF inhibition pericytes in tumour cells less sensitive to VEGF inhibition VASCULAR MIMICKING- tumour cells pretend to be blood vessel cells, so they form vessels themselves

Question 25

main strategy now to to target tumour angiogenesis

Answer 25

needs to have balance- don’t block everything (otherwise tumour produces other factors/chemotherapy can’t get to tumour as no vessels), but reduce vessels enough ie NORMALISE blood vessels

Question 26

single cell RNA sequencing of tumour endothelium

Answer 26

take a bit of brain ie tumour, and use this method to identify all the genes in a single tumour cell, and compare to normal cells- identifies NON-VGEF targets

Question 27

age-related macular degeneration and treatment

Answer 27

CHOROIDAL blood vessels grow which are leaky, causing oedema= visual impairment another anti-VGEF called VEGF used for this

Question 28

organ on a chip, tumour on a chip and clinical significance

Answer 28

where 3D cells are grown in culture, and we create own perfusion and drainage in a lab to understand their behaviour better can do the same for tumour cells, and thus understand what drugs work best