Angiogenesis: role of VEGF and Hypoxia (Part 1 & 2) Flashcards
What is vasculogenesis?
embryonic formation of endothelial cells from mesoderm that form new blood vessels in blood islands
-give rise to heart and first primitive vascular plexus inside the embryo
What is angiogenesis?
needed to fully form the vascular network
-process by which new blood vessels form from pre-existing vessels formed in vasculogenesis
what is inside the angiogenetic cluster?
blood cells
Where are the first blood islands?
in the yolk sac
What is sprouting angiogenesis?
when tissues that have low nutrient and oxygen supply produce VEGF-A and induce endothelial cells to secrete proteases that degrade basement membrane and allow endothelial cells to escape original blood vessels
-form sprouts to neighboring cells
-extend toward the source of angiogenic signal (VEGF-A)
What does VEGF do in sprouting angiogenesis?
induce the secretion of proteases that will degrade basement membrane and allow endothelial cells to escape their original vessel walls
-they will proliferate and form sprouts connecting neighboring vessels
What is intussusceptive (splitting) angiogenesis?
formation of new blood vessels by splitting of preexisting vessel into two
Does angiogenesis continue after birth?
yes, it happens every month with periods and happens when you are healing wounds
What is the tunica interna?
endothelial cells that line arteries and veins
What is the tunica media?
layer of smooth muscle in arteries and veins
What is the tunica externa?
outside layer of arteries and veins made of elastin and collagen
Is smooth muscle layer thicker in veins or arteries?
arteries
What are capillaries made of?
only endothelial cells
-no muscle or elastin & collagen
What are pericytes?
support cells that wrap around capillaries that regulate permeability of capillaries they surround
What are the three types of capillaries?
continuous
fenestrated
sinusoid
continuous capillary
basement membrane is continuous (would be in blood brain barrier)
fenestrated capillary
has fenestrations on the endothelial layer
sinusoid capillary
incomplete basement membrane & intercellular gaps on endothelial layer (liver-areas w/ lots of blood flow)
What determines the type of capillary that is present?
the tissue type and the amount of interaction with blood
Growth factors in vasculogenesis:
VEGF and FGF
Growth factors in mature vessels:
Ang1 (stabilize blood vessel)
Growth factors in angiogenesis:
VEGF
Growth factors in mature circulatory system:
PDGF and TGF-b
Is VEGF a required angiogenic growth factor?
yes
Is blocking VEGF lethal?
yes
is blocking 50% of VEGF lethal?
yes
Major form of VEGF and its receptor:
VEGF-A and VEGFR2
-involved in both vasculogenesis and angiogenesis
are there different forms of VEGF and its receptor?
yes- do not need to know specifics
What is the tip cell?
the end of the sprouting capillary that is seeking out VEGF
What is the cell that forms the tube of the sprouting capillary?
stalk cell
What induces sprouting angiogenesis?
hypoxia
What is present during hypoxic states that stimulates the start of sprouting angiogenesis?
hypoxia inducible factor (HIF)
What does HIF do?
cause cell to release VEGF
Why does HIF induce sprouting angiogenesis?
causes the capillaries to sprout towards the part that does not have enough oxygen
-creates capillary interactions that bring oxygen to those spots that are lacking
What occurs to HIF during normoxia conditions?
HIF-a is hydroxylated and does not bind to HIF-b
-HIF-a binds to pVHL
-HIF-a gets ubiquitinated
-go to proteasome for degradation
What occurs to HIF during hypoxic conditions?
HIF-a transported to nucleus where it binds to HIF-b
-binds to DNA and causes release of VEGF
What inhibits Tie-2?
Ang-2
-allows for VEGF-A induced cell migration & division
What supports Tie-2?
Ang-1
-in stable blood vessels (normoxia conditions)
What does angiogenesis require of capillaries?
destabilization
-allow for more growing and migration
What are the two oxygen sensing domains of HIF-1a?
PHD2 and FIH
-oxygenated and tag for degradation (PHD2) or inactivation (FIH)
-work at different levels of oxygen (lose PHD2 first-slightly hypoxic)
What is N-TAD involved with?
blocking the oxygenation of PHD
What is C-TAD involved with?
blocking both PHD and FIH
What does Ang-1 promote?
vessel maturation by stimulating migration, adhesion, and survival of endothelial cells
*stability
What does Ang-2 promote?
disruption of connections between endothelium and perivascular cells
When Ang-2 and VEGF work together, what happens?
neovascularization
What does Ang-2 say to Ang-1?
hey get outta here
Where is Ang-1 usually made?
pericytes
Where is Ang-2 usually made?
endothelial cells
When Ang1 and Tie2 associate, what is occurring ?
the cell is maintaining integrity and quiescence
Where is ang-2 stored in endothelial cells?
Weibel-Palade bodies
what causes Ang-2 to be released from WPB?
inflammatory stimulus
where is Ang-2 normally expressed?
in the tip cells of angiogenic sprouts
What is PDGF?
released from tip cell and stimulates proliferation of the pericyte cells and smooth muscle cells
are vasculogenesis & angiogenesis required for healing of bone?
yes
Outline endochondral bone formation:
-start with just capillaries
-cartilage forms from hypertrophic chondrocytes
-blood vessels form in between the hypertrophic chondrocytes
-attract osteoblasts and form bone that eventually replace the cartilage
Steps of bone regrowth following fracture:
-hematoma (day 0-5)
-soft unmineralized cartilage (5-10)
-fibrous tissue (10-16)
-hard callus/ secondary bone (16-21)
-hard callus/ remodeled bone (21-35)
What does Fit-IgG do?
inhibit VEGF from working in broken bone
Does osteoporosis speed up or slow down fracture healing?
slow down
What are hemangiomas?
benign proliferative lesions that are localized growths of capillary endothelium
-up to 10% of all babies
-caused by mutation in TEM8 or VEGFR2 genes
How do tumors become vascularized?
the tumor cells release VEGF which bind to VEGFR and cause capillaries to move towards them
What do endostatin and angiostatin do?
decrease proliferation and migration and increase apoptosis in endothelial cells
also decrease the release of VEGF from tumor cells
-inhibit angiogenesis
What is endostatin?
anti-angiogenic agent
-naturally occurring C-terminal fragment of type 18 collagen
What is angiostatin?
38 kDa fragment of plasmin
Why are anti-angiogenic treatments used in cancer?
designed to prevent the formation of new blood vessels to tumors
-do not completely eradicate
-would need combination of drugs
How does bevacizumab work?
it is a monoclonal antibody that binds to VEGF and does not allow interaction with VEGFR
What is a type of anti-angiogenic drug that is in
clinical development?
tyrosine kinase inhibitors
Where do type 1 tyrosine kinase inhibitors bind?
-bind in ATP binding cleft (active site)
Where do type 2 tyrosine kinase inhibitors bind?
hydrophobic region adjacent to ATP binding cleft
-steric inhibition
What is macular degeneration?
chronic eye disease that causes vision loss in the center of your field of vision
Using VEGF inhibition does what to tumors ?
decreasing vascular supply and will cause tumor to decrease in size
VEGFA and VEGFR2 are involved in…
vasculargenesis and angiogenesis
