Angiogenesis Role of VEGF and Hypoxia Flashcards
what is vasculogenesis
de novo formation of blood vessels when there are no existing ones in the vicinity
what often pairs with vasculogenesis and why
angiogenesis, it is needed to fully form the vascular network
what does vasculogenesis give rise to in the fetus
the heart and the first primitive vascular plexus and its surrounding membranes
what happens in vasculogenesis
angiogenic cell clusters form blood islands in the yolk sac and these clusters give rise to red blood cells
what are the 2 sites that the vascular system forms in the embyro
the blood island of the yolk sac and one in the embryo proper
what is angiogeneis
the process by which new blood vessels form from pre-existing vessels that are formed in the early stages of vasculogenesis
what are the 2 types of angiogenesis
sprouting angiogenesis and intussusceptive angiogenesis
what is sprouting angiogenesis
tissues that have low nutrient and oxygen supply produce signals (VEGF-A) that induces endothelial cells to secrete proteases that degreade their BM and allow the endothelial cells to escape their original vessel walls. the cells proliferate and form sprouts connecting to neighboring vessels. extend towards the source of the angiogenic signal
what is intussusceptive angiogenesis
also known as splitting angiogenesis and is the formation of new vessels by splitting a pre-existing vessel in 2
- allows for increase in number of capillaries without an increase in endothelial cells
where does angiogenesis take place in adults
-in women when the lining of the uterus is shed during the menstrual cycle new blood vessels are formed
- wound repair
what is in the interior of the blood vessel
single layer of endothelial cells attached to and separated from the outer layers by the basal lamina
what makes up the blood vessel
loose CT outer layer, smooth muscle middle layer, and endothelial cells
what are the largest blood vessels? smallest?
largest- arteries and veins
smallest- capillaries and sinusoids
what do capillaries and sinusoids consist of?
endothelial cells and a basal lamina with scattered pericytes
what are pericytes
members of CT family, related to vascular SM cells that wrap themselves around the small vessels
what is the difference between arteries and veins
- veins have a larger lumen
- veins have a thinner external and middle layer
what makes up the wall of a capillary
a single layer of endothelial cells
what are the 3 types of capillaries
continuous, fenestrated and sinusoid
describe a continuous capillary
-solid synctitium of endothelial cells joined by junctions
describe a fenestrated capillary
have holes in the endothelial cells where material can move back and forth
describe a sinusoid capillary
gaps between endothelial cells and the basement membrane
what is pO2
a measure of how much O2 is dissolved in the blood
how many molecules of O2 can hemoglobin bind
4
what does BPG do to hemoglobin
decreases O2 affinity, O2 moves from Hb into plasma and into tissue
what would a right shift in hemoglobin affinity of O2 be caused by
-increased H+
-increased BPG
- increase temperature
- increased altitude
what would a left shift in hemoglobin affinity for O2 be caused by
- decreased H+
- decreased BPG
- decreased temperature
- decreased HbF
- decreased CO
- decreased MetHb
what does the oxygen binding/dissociated plot for hemoglobin say
beyond 95% saturation, Hb will dissolve O2
what paracrine factors are used in vasculogenesis and what do they give rise to
FGF2- mesoderm cells
VEGF- hemangioblasts which form tubes
what does ANG1 bind to and what happens
binds to tie-2 on the endothelial cell of the pericyte and maintains vessel integrity and quiescence
what is the paracrine factor in angiogenesis
VEGF
what does VEGF in angiogenesis do
produces a juvenile vascular system by sprouting and splitting
what paracrine factors does the mature circulatory system use
PDGF and TGFbeta
what do PDGF and TGFbeta do
maturation and remodeling to produce a mature vascular system
what do antibodies against VEGF block
embyronic development
- bone morphogenesis
- female reproductive cycling
- corneal angiogenesis
- growth of several tumor types in animal models
what happens when VEGF is blockes in embryonic development
it is legal even a 50% reduction
what type of receptors are VEGF receptors
tyrosine kinase receptors
what does VEGF-A bind to and what does it regulate
binds to VEGFR-1 and VEGFR-2 and regulates vasculogenesis, angiogenesis, inflammatory responses, and carcinogenesis
what does VEGFR-1 modulate
placenta and macrophages and vasculogenesis and angiogensis
what does VEGFR-2 modulate
vasculogenesis and angiogenesis
what does VEGFR-3 modulate
lymphangiogenesis
what do pseudopodial processes do
guide the development of the capillary sprout as it grows into the surrounding tissue
what happens with angiogenesis when O2 levels are low
results in high HIF which induces cells to secrete VEGF. VEGF then stimulates capillary sprouting and angiogenesis
what happens with angiogenesis when O2 levels are high
HIF is low so not VEGF gets secreted for angiogenesis
what senses O2 levels
HIF (hypoxia induced factor)
what regulates HIF-1
pVHL- von hippel lindau tumor suppressor
what happens with HIF mechanistically with hypoxia
moves into the nucleus to express VEGF to stimulate angiogenesis
what happens with HIF mechanistically with normoxia
O2 hydroxylates HIF-1alpha then binds to a pVHL which degrades HIF-1 by ubiquidination
what enzyme catalyzes the degradation of HIF-1alpha in normoxia
prolyl hydroxylases
what 3 levels is VEGF-A expression controlled at
transcription, messenger RNA, stability, and translation
what angiogenic factors are induced by hypoxia
VEGF-A and Ang-2
what happens when VEGF-A and Ang-2 bind in hypoxia
Tie-2 and VEGFR2 are recruited and this leads to sprouting angiogenesis
what happens with ANG-1
Tie-2 is signaled which activates a notch pathway which results in quiescence of the endothelial cell (nothing happens)
what inhibits ANG-1
ANG-2
what do HIF prolyl hydroxylase and HIF asparaginyl-hydroxylase do
they lead to inactivation and protosomal degradation of both domains of HIF-1alpha
what portion of genes of HIF-1alpha are activated with low hypoxia
the N-TAD genes
(amino terminal activation domain)
what portion of genes of HIF- 1 alpha are activated with high hypoxia
the N-TAD genes and the C-TAD genes (carboxy-terminal activation domain)
what does ANG-1 promote
vessel maturation by stimulating migration adhesion and survival of endothelial cells
what does ANG 2 do
-depends on if VEGF is present
- antagonist of Ang-1 and blocks its ability to bind to Tie-2 receptor
- disrupts connections between the endothelium and perivascular cells
- with VEGF ANG-2 promotes neo-vascularization
what releases ANG-1
pericytes
what does binding of ANG-1 to Tie-2 do
promotes vessel integrity, inhibits vascular leakage and suppresses inflammatory gene expression, stabilizing tight junctions in endothelial cells
when is ANG-2 released and what is it stored in
during hypoxia, stored in weibel palade bodies
what does ANG-1 do
promotes quiesence and stability of vessels
what does ANG-2 do
stimulates sprouting
what do tip cells do
get induced by ANG-2 to start the migration process
what part of the cell do ANG-2 and VEGF act on
the tip
how does PDGF stimulate proliferation of pericytes and smooth muscle cells
PDGF is synthesized and secreted by tip cells. PDGF binds to HSPG which makes pericytes come in and bind to endothelial cell layer and surround the vessel
what happens in endochondral bone formation
-mesenchymal cells lay down avascular cartilage
-these differentiate into hypertrophic chondrocytes which signal to vascularize the forming bone
- then you get long bone with different layers of chondrocytes with bone marrow and vascularization
what are the stages of bone fracture repair
hematoma ->soft callus -> fibrous tissue ->hard callus -> remodeling
how does fracture repair involve VEGF
it is required for repair
how is fracture healing impaired in osteoporosis
it takes longer and doesnt heal as well
what is a hemangioma
benign highly proliferative lesions involving abberant localized growth of capillary endothelium . caused by TEM8 or VEGFR2 genes. benign
what happens as tumors grow
they produce large quantities of VEGF
what does VEGF recuit in tumors
lymphatics and angiogenesis factors to create own blood supply, ANG1 ANG2, and TDGF
what is the environment of tumors and what does this recuit
hypoxic, recruits HIF 1 alpha
what are the naturally occuring inhibitors of angiogenesis
endostatin and angiostatin
what do endostatin and angiostatin do when they bind to endothelial cells
promote apoptosis and inhibit proliferation and migration
what do endostatin and angiostatin do when they bind to tumor cells
down regulate VEGF
what is endostatin dervied from
type 18 collagen
how is endostatin released
from the breakdown of type 18 collagen
what is angiostatin derived from
plasmin (derived from plasminogen) that gets broken down into kringle fragments
what are angiogenesis inhibitors designed to prevent
formatino of new blood vessels which stops growth and spread of tumors
how is endostatin treatment effective
in doses until tumor doesnt grow
what is the mechanism of some anti-cancer angiogenesis inhibitors
they eliminate the activity of a binding domain so when the ligand binds, nothing happens. tyrosine kinase inhibitors
what is macular degeneration
chronic eye disease that causes vision loss in the center of your field of vision. caused by deterioration of the macula
where do tumors grow in the eye
iris because it is highly vascularized
what does PGI2 do
inhibits platelet activation and is an effective vasodilator
what does eNOS do
generates NO in the vascular endothelium, rates vascular tone, cellular proliferation, leukocyte adhesion, and platelet aggregation
what does NO do
powerful vasodilator with a short half life, intercellular messenger that relaxes smooth muscle
what do endothelins do
constrict blood vessels and raise BP
where are VEGF receptors found
on the membrane
