Angiogenesis: Role of VEGF and Hypoxia Flashcards
vasculogenesis
the embryonic formation of endothelial cells from the mesoderm layer precursors to form new blood vessels in blood islands
vasculogenesis is often paired with
angiogenesis
angiogenesis is needed to fully form
the vascular network
vasculogenesis gives rise to (2)
the heart and the first primitive vascular plexus inside the embryo and in its surrounding membranes
where does the vascular system form in the embryo? (2)
blood islands of the yolk sac
embryo proper
angiogenesis
the process by which new blood vessels form from pre-existing vessels that are formed in the early stages of vasculogenesis
two types of angiogenesis
sprouting angiogenesis
intussusceptive angiogenesis
sprouting angiogenesis
tissues that have low nutrient and oxygen supply will produce signals (VEGF-A) that induces endothelial cells to secrete proteases that degrade their basement membranes and allow the endothelial cells to escape their original vessel walls. These cells continue to proliferate and form sprouts connecting neighboring vessels, guided by extending towards the source of the angiogenic signal
intussusceptive angiogenesis
also known as splitting angiogenesis is the formation of new vessels by splitting a pre-existing vessel in two
example of angiogenesis in women
menstruation, each month for a few days in the lining of the uterus during the menstrual cycle as new blood vessels are formed
another example of angiogenesis
would repair
The largest of the blood vessels are the (2)
arteries and veins
arteries and veins have a tough, thick layer of (2)
connective tissue and many smooth muscle cells
The thickness of these layers varies depending upon the (2)
diameter and function of the vessel
The interior of the blood vessel consists of
single layer of endothelial cells attached to and separated from the outer layers by the basal lamina
The finest branches of the vasculature are the (2)
capillaries and sinusoids
These consist of only (3)
endothelial cells and a basal lamina together with a few scattered pericytes
These cells are members of the connective-tissue family, related to
vascular smooth muscle cells
Pericytes wrap themselves around
the small vessels and have other important functions
capillaries are very thin, composed of
a single layer of endothelial cells
what is the main role of circulation?
supplying oxygen to tissues
pO2 is a measure of
how much O2 is dissolved in the blood
hemoglobin contained in RBCs can bind up to
4 molecules of O2
neutralizing antibodies against VEGF block (5)
embryonic development bone morphogenesis females reproductive cycling corneal angiogenesis growth of several tumor types in animal models
VEGF is required for
embryonic development
blocking VEGF is
lethal
even a 50% reduction of VEGF is
lethal
VEGF is required for
developmental angiogenesis
what type of receptors are VEGF receptors are
tyrosine kinase receptors
VEGF-a
a major contributor to angiogenesis, bind and activates VEGFR1 and VEGF2 and regulates vasculogenesis, angiogenesis, inflammatory responses, and carcinogenesis
The soluble form of VEGFR-1 appears to be an important modulator for the
placental vasculature
VEGF-C and -D mainly activate VEGFR-3 and regulate
lymphangiogenesis
The extracellular domain of VEGFR-3 is once cleaved and joined with
disulfide bond
pseudopodial processes guide the development of the
capillary spout as it grows into the surrounding tissue
hypoxia induces
spouting angiogenesis
when oxygen concentration drops, this acts as a stimulus trigger to induce the transcription and secretion of
VEGF by the hypoxic cells
VEGF then acts to stimulate
capillary sprouting and angiogenesis, reversing the hypoxia
VEGF-a expression is controlled at which three levels?
transcription
mRNA stability
translation
ang-1 promotes vessel maturation by stimulating (3)
migration, adhesion, and survival of endothelial cells
ang-2 has different effects depending upon whether
VEGF is present or not
importantly, ang-2 is an antagonist of
ang-1 and blocks its ability to bind to the tie-2-receptor
ang-2 disrupts connections between the
endothelium and perivascular cells
in combination with VEGF, ang-2 promotes
neo-vascularization
PDGF stimulates proliferation of
pericytes and smooth muscle cells
what is absolutely required for successful fracture healing of bone?
vasculogenesis/angiogenesis
endochondral bone formation mechanism
condensation of mesenchymal cells which form cartilage in the presence of a vascular bed. form hypertrophic chondrocytes which put down a cartilaginous matrix that turns into bone
femur fracture repair
initially forms a hematoma
soft callus/unmineralized cartilage is deposited by chondrocytes
vascular angiogenesis forms fibrous tissue
cartilage is replaced with new bone to form hard callus/secondary bone
hard callus/remodeled bone
healing in younger individuals is quicker than
healing in older individuals
fracture healing requires
VEGF
fracture healing in osteoporotic bone vs normal bone
healing is delayed significantly, bone doesn’t achieve the same level of mechanical stability as normal individuals. this is a contributor to morbidity/fatality associated with osteoporosis
hemangioma, hereditary capillary
begins highly proliferative lesions involving aberrant localized growth of capillary endothelium. they are the most common tumor in infancy occurring in up to 10% of all babies
hemangioma is caused by
a gremlin mutation in TEM8 (a tumor specific endothelial cell marker) or VEGFR2 genes
hallmark of tumor development
angiogenesis
(tumors need independent blood supply as they grow so they secrete VEGF and other growth factors for angiogenesis
3 essential ways that VEGF may affect tumor vasculature?
?
VEGFR1
VEGFR2
VEGFR3
1: stalk of endothelium
2: stalk of endothelium
3: lymphatic endothelial cell
what happens when tumor cells secrete VEGF?
cancer cell secretes VEGF, binds to receptor, initiates relay proteins/intracellular 2nd messengers which stimulate new endothelial growth or stimulate growth of the tumor itself
endostatin and angiostatin target
endothelial and tumor cells
endostatin and angiostatin lead to
inhibition of angiogenesis
how is angiogenesis inhibited by endostatin and angiostatin? (2)
down regulate proliferation migration
upregulate apoptosis
down regulation of VEGF
problem with endostatin and angiostatin
they’re not specific to the tumor cells, so they may have consequences such as stopping angiogenesis where/when we need it
endostatin
naturally occurring, 20 kDa C-terminal fragment derived from type 18 collagen
endostatin is reported to serve as an
anti-angiogenic agent, similar to angiostatin and thrombospondin
angiostatin
38 kDa fragment of a larger protein, plasmin
plasmin
fragment of plasminogen
what are angiogenesis inhibitors designed to prevent?
the formation of new blood vessels, thereby stopping or slowing the growth or spread of tumors
has the US food and drug administration approved any angiogenesis inhibitors for the treatment of cancer?
yes, several
side effects of angiogenesis (different than other cancer treatments) (4)
bleeding
clots in arteries
hypertension
protein in urine
do angiogenesis inhibitors eradicate cancer?
no, they only stop or slow the growth of cancer
bevacizumab (Avastin)
monoclonal antibody that specifically recognizes and binds to VEGF. When VEGF is attached to bevacizumab, it is unable to activate the VEGF receptor. Other angiogenesis inhibitors, including sorafenib and sunitinib, bind to receptors on the surface of endothelial cells or to other proteins in the downstream signaling pathways, blocking the intracellular signaling activities of tyrosine kinase receptors like VEGF receptor.
bevacizumab (Avastin) simple mechanism
VEGF is unable to bind to its receptor
what type of receptors are VEGFR?
tyrosine kinase
mechanism of action of some anti-cancer angiogenesis inhibitors
tyrosine kinase inhibitors which mimic the design of ???? (non competitive inhibitor)
dry macular degeneration
chronic eye disease that causes vision loss in the center of your field of vision
dry macular degeneration is marked by deterioration of the
macula
macula
the center of the retina, the layer of tissue on the inside back wall of your eyeball
wet macular degeneration
inappropriate angiogenesis occurring in the retina
leakage of blood/fluid into the center of the retina, results in blindness
what is the general vascular system of the chorioallantoic membrane of a chick used for?
assay materials for angiogenic properties
yolk sac
One monoclonal antibody therapy is approved to treat
age-related macular degeneration (AMD)
age-related macular degeneration (AMD)
a progessive eye diease that results in loss of central vision, and is the leading cause of severe vision loss in adults over the age of 65
the wet form of AMD accounts for –% of cases
10%
the wet form of AMD is characterized by
the abnormal growth of new blood vessels, which leak fluid and blood, inducing scar formation and destroying vision
examples of monoclonal antibody therapy (2)
Ranibizumab
Genentech
Genentech
A recombinant humanized IgG1 kappa monoclonal antibody fragment that binds vascular endothelial growth factor-A (VEGF-A) and cleavage products, and prevents their interaction with VEGF receptors (VEGFR-1 and VEGFR-2), thereby inhibiting endothelial cell proliferation, angiogenesis, and vasular leakage in the retina and choroidal layers.
Genentech is approved for (2)
neovascular (wet) age-related macular degeneration
macular edema after retinal vein occlusion
how is Genentech administered?
by intravitreal injection
