angiogenesis Flashcards
hypoxia
low oxygen on tissue
what do cancers need to grow?
oxygen, glucose, amino acids, vascular system
what is a pericyte?
support cell for small vessels
what is the stroma made of
fibroblasts and other cell types
what happens at the cell cell junctions of endothelial cells?
there is increased permeability so cells can leave the blood as well as fluids and solutes
what does it mean when you say oxygen has a diffusive limit
it cannot diffuse forever
how close are cells to a blood vessel in the venous end
10µm because the blood is deoxygenated so we need a short diffusion distance
how close are cells to a blood vessel in the arterial end
70µm because the blood is oxygenated
how do cancers stay oxygenated (6)
- induce vasodilation
- sprouting angiogenesis
- intussusceptive angiogenesis
- anaerobic metabolism
- vascular co-option
- vasculogenesis
what is intussusceptive angiogenesis
splitting existing blood vessels
what is vascular co-option?
when cancers grow along blood vessels
what is vasculogenesis
developing new vessels de novo (spontaneously)
what does VEGF stand for
vascular endothelial growth factor
what does VEGF do
makes vascular endothelial cells grow
VEGF-A structure
glycosylated protein, 121-189 amino acids long
summary of the process of angiogenesis
VEGF production and secretion, endothelial activation - binds to a receptor and induces Ca2+ uptake in the cell and other cellular pathways. Increase in permeability, matrix degradation, this allows pericyte withdrawal, new blood vessel spout forms and endothelial migration occurs, cell division behind migrating sprout, lumen formation, sprout connection and blood flow
what
It also activates standard map kinase ras signalling
what happens to the O2 in the cell as it proliferates
the amount of it is reduced
what does the reduction of O2 in the cell activate
Transcription factor HIF1 (hypoxia inducible factor)
what happens when HIF1 is activated
translocated to nucleus and turns on and off any genes, including VEGF, VEGF is produced and secreted, it activates VEGFR (VEGF receptor) which activates endothelial cells
what are the different isoforms of HIF1
HIF1-α and HIF1-β
what happens to HIF1-α in normal conditions
it is rapidly degraded by oxygen
what happens to HIF1-α in hypoxic conditions
it binds to HIF1-β to form a
transcription factor complex which has slowed degradation
what is the hypoxia response element
region of DNA with a particular sequence that the HIF complex can recognise
what happens when the HIF complex comes across the hypoxia response element
it binds to the sequence and then further transcription factors can bind and form a big complex which can go along and make mRNA for protein production
what TF binds after the HIF complex binds
TBP (Tata binding protein)
what does TBP do
finds the polymerase II
what happens when TBP and polymerase II bind
they can turn genes on and off
what happens to glucose transporters in hypoxia
they can be turned on and off so that the cell can overload itself with glucose so it can respire by glycolysis
how are the effects of VEGF reduced
with a VEGF antibody
how does VEGF cause leakiness
- blood flow (more blood more leak)
- angiogenesis - growing more leaky blood vessels
- increase vascular permeability (make specific vessels leaky)
what does the VEGF mechanism depend on
Ca2+
how does VEGF weaken vessel walls
it enhances proteinase activity
what happens in pericyte withdrawal
the pericytes move away from the blood vessel, creating space for the endothelial cells to migrate
intussusception (1st type of angiogenesis)
fibroblasts and pericytes push in on endothelial cell and so it becomes 2 separate vessels which move apart
sprouting angiogenesis (2nd type)
endothelial cells put out filopodia towards sources of VEGF (tip cell)
which cells divide in sprouting angiogenesis
the stalk cells (directly behind the tip cell)
how does only one sprout occur and not many
tip cells repress the cells around them and stop them from being able to become tip cells
what happens when 2 filopodia meet
they signal to the other cells that they have found another tip cell, the sprouts grow closer to each other and then the tip cells differentiate into endothelial cells to make a vascular loop
what does angiopoietin 1 (ang1) do
stabilises vessels, opposite of VEGF
what does angiopoietin 2 (ang2) do
destabilises vessels, blocks effects of ang1
what does platelet derived growth factor do (PDGF)
recruits pericytes
what is bevacizumab (Avastin)
a drug that binds to circulating VEGF
what is Ramucirumab
an antibody that binds to the VEGF receptor, inhibiting its activation
