Angiogenesis: role of VEGF and Hypoxia (Part 1 & 2) Flashcards

1
Q

What is vasculogenesis?

A

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

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2
Q

What is angiogenesis?

A

needed to fully form the vascular network
-process by which new blood vessels form from pre-existing vessels formed in vasculogenesis

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3
Q

what is inside the angiogenetic cluster?

A

blood cells

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4
Q

Where are the first blood islands?

A

in the yolk sac

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5
Q

What is sprouting angiogenesis?

A

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)

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6
Q

What does VEGF do in sprouting angiogenesis?

A

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

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7
Q

What is intussusceptive (splitting) angiogenesis?

A

formation of new blood vessels by splitting of preexisting vessel into two

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8
Q

Does angiogenesis continue after birth?

A

yes, it happens every month with periods and happens when you are healing wounds

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9
Q

What is the tunica interna?

A

endothelial cells that line arteries and veins

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10
Q

What is the tunica media?

A

layer of smooth muscle in arteries and veins

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11
Q

What is the tunica externa?

A

outside layer of arteries and veins made of elastin and collagen

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12
Q

Is smooth muscle layer thicker in veins or arteries?

A

arteries

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13
Q

What are capillaries made of?

A

only endothelial cells
-no muscle or elastin & collagen

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14
Q

What are pericytes?

A

support cells that wrap around capillaries that regulate permeability of capillaries they surround

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15
Q

What are the three types of capillaries?

A

continuous
fenestrated
sinusoid

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16
Q

continuous capillary

A

basement membrane is continuous (would be in blood brain barrier)

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17
Q

fenestrated capillary

A

has fenestrations on the endothelial layer

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18
Q

sinusoid capillary

A

incomplete basement membrane & intercellular gaps on endothelial layer (liver-areas w/ lots of blood flow)

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19
Q

What determines the type of capillary that is present?

A

the tissue type and the amount of interaction with blood

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20
Q

Growth factors in vasculogenesis:

A

VEGF and FGF

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21
Q

Growth factors in mature vessels:

A

Ang1 (stabilize blood vessel)

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22
Q

Growth factors in angiogenesis:

A

VEGF

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23
Q

Growth factors in mature circulatory system:

A

PDGF and TGF-b

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24
Q

Is VEGF a required angiogenic growth factor?

A

yes

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25
Q

Is blocking VEGF lethal?

A

yes

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26
Q

is blocking 50% of VEGF lethal?

A

yes

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27
Q

Major form of VEGF and its receptor:

A

VEGF-A and VEGFR2
-involved in both vasculogenesis and angiogenesis

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28
Q

are there different forms of VEGF and its receptor?

A

yes- do not need to know specifics

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29
Q

What is the tip cell?

A

the end of the sprouting capillary that is seeking out VEGF

30
Q

What is the cell that forms the tube of the sprouting capillary?

A

stalk cell

31
Q

What induces sprouting angiogenesis?

A

hypoxia

32
Q

What is present during hypoxic states that stimulates the start of sprouting angiogenesis?

A

hypoxia inducible factor (HIF)

33
Q

What does HIF do?

A

cause cell to release VEGF

34
Q

Why does HIF induce sprouting angiogenesis?

A

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

35
Q

What occurs to HIF during normoxia conditions?

A

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

36
Q

What occurs to HIF during hypoxic conditions?

A

HIF-a transported to nucleus where it binds to HIF-b
-binds to DNA and causes release of VEGF

37
Q

What inhibits Tie-2?

A

Ang-2
-allows for VEGF-A induced cell migration & division

38
Q

What supports Tie-2?

A

Ang-1
-in stable blood vessels (normoxia conditions)

39
Q

What does angiogenesis require of capillaries?

A

destabilization
-allow for more growing and migration

40
Q

What are the two oxygen sensing domains of HIF-1a?

A

PHD2 and FIH
-oxygenated and tag for degradation (PHD2) or inactivation (FIH)
-work at different levels of oxygen (lose PHD2 first-slightly hypoxic)

41
Q

What is N-TAD involved with?

A

blocking the oxygenation of PHD

42
Q

What is C-TAD involved with?

A

blocking both PHD and FIH

43
Q

What does Ang-1 promote?

A

vessel maturation by stimulating migration, adhesion, and survival of endothelial cells
*stability

44
Q

What does Ang-2 promote?

A

disruption of connections between endothelium and perivascular cells

45
Q

When Ang-2 and VEGF work together, what happens?

A

neovascularization

46
Q

What does Ang-2 say to Ang-1?

A

hey get outta here

47
Q

Where is Ang-1 usually made?

A

pericytes

48
Q

Where is Ang-2 usually made?

A

endothelial cells

49
Q

When Ang1 and Tie2 associate, what is occurring ?

A

the cell is maintaining integrity and quiescence

50
Q

Where is ang-2 stored in endothelial cells?

A

Weibel-Palade bodies

51
Q

what causes Ang-2 to be released from WPB?

A

inflammatory stimulus

52
Q

where is Ang-2 normally expressed?

A

in the tip cells of angiogenic sprouts

53
Q

What is PDGF?

A

released from tip cell and stimulates proliferation of the pericyte cells and smooth muscle cells

54
Q

are vasculogenesis & angiogenesis required for healing of bone?

A

yes

55
Q

Outline endochondral bone formation:

A

-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

56
Q

Steps of bone regrowth following fracture:

A

-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)

57
Q

What does Fit-IgG do?

A

inhibit VEGF from working in broken bone

58
Q

Does osteoporosis speed up or slow down fracture healing?

A

slow down

59
Q

What are hemangiomas?

A

benign proliferative lesions that are localized growths of capillary endothelium
-up to 10% of all babies
-caused by mutation in TEM8 or VEGFR2 genes

60
Q

How do tumors become vascularized?

A

the tumor cells release VEGF which bind to VEGFR and cause capillaries to move towards them

61
Q

What do endostatin and angiostatin do?

A

decrease proliferation and migration and increase apoptosis in endothelial cells
also decrease the release of VEGF from tumor cells
-inhibit angiogenesis

62
Q

What is endostatin?

A

anti-angiogenic agent
-naturally occurring C-terminal fragment of type 18 collagen

63
Q

What is angiostatin?

A

38 kDa fragment of plasmin

64
Q

Why are anti-angiogenic treatments used in cancer?

A

designed to prevent the formation of new blood vessels to tumors
-do not completely eradicate
-would need combination of drugs

65
Q

How does bevacizumab work?

A

it is a monoclonal antibody that binds to VEGF and does not allow interaction with VEGFR

66
Q

What is a type of anti-angiogenic drug that is in
clinical development?

A

tyrosine kinase inhibitors

67
Q

Where do type 1 tyrosine kinase inhibitors bind?

A

-bind in ATP binding cleft (active site)

68
Q

Where do type 2 tyrosine kinase inhibitors bind?

A

hydrophobic region adjacent to ATP binding cleft
-steric inhibition

69
Q

What is macular degeneration?

A

chronic eye disease that causes vision loss in the center of your field of vision

70
Q

Using VEGF inhibition does what to tumors ?

A

decreasing vascular supply and will cause tumor to decrease in size

71
Q

VEGFA and VEGFR2 are involved in…

A

vasculargenesis and angiogenesis