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59 Cards in this Set

  • Front
  • Back
Angiogenesis
formation of new blood vessels from an existing vascular bed
Too much AG -->
cancer
diabetes
atherosclerosis
psoriasis
Too little AG -->
baldness
ischemic heart disease
stroke
blood clots
limb fractures
Mechanism overview
Tip Cell selection
Tip Cell navigation
Stalk cell elongation - lumen morphogenesis
Anastamosis (of 2 TC)
Maturation & stabilisation
in vitro models
EC on:
23 substrata + VEGF
matrigel
in vivo models
CAM assay
zebrafish
cornea assay
etc
AG activators
VEGF, PLGF, VEGFR
Ang 1 & Tie 2
PDGF - BB and Rs
FGF, HGF
TGFbeta1, endoglin TGFbeta
Ephrins
MMPs, heparanase
NOS, cyclooxygenase
Integrins
AG Inhibitors
VEGFR1, sVEGFR1, neurophillin
Angiopoietin 2
TSP-1, TSP-2
Angiostatin
Endostatin
Restin
TIMPs, MMP Is
Maspin
mice with EC deletion of Dicer
defective postnatal AG
pro-angiomiRs
promote AG via targeting negative regulators

e.g miR-126

vis versa
Hypoxia activates ______ which activates _______ __ __________ ______
HIF
trx of pro-angiogenic factors (VEGF)
KO VEGF/VEGFR
no EC

embryonic lethal
Haploinsufficiency
KO VEGFR1
Excess EC

no tube/vessel formed
KO ANG1/TIE2
No Pericytes
VEGF
homodimeric glycoprotein

VEGF-A (main one) - splice varients
VEGF, B, C, D PlGF

diff species bind to different Rs with diff AFFINITES
VEGFR
1
2
3
Neuropilin 1 & 2

*not EC specific* oooooooooo
'b' variants of VEGFA
ANTI-ANGIOGENIC

differ by 6aa @ C terminal - affects ability to bind Rs
VEGF A function
Vasculogenesis
ANGIOGENESIS
VEGF B function
Coronary vascularisation and growth

KO-> smaller heart
VEGF C function
lymphatic development
activates TC
PlGF function
Vascular remodelling in ADULTS and disease
not necessary for development!
Predominant isoforms of VEGF A
165 (has heparin binding domain -> matrix)

121 (freely diffusible)
VEGFR 1
vascular development
haematopoietic cell recruitment to new blood vessels
decoy receptor
*VEGFR 2
vasculogenesis & angiogenesis
EC permeability, migration, proliferation, differentiation
TC SELECTION
VEGFR 3
lymphanogenesis
autophosphorylation Tyr sites on VEGFR2
951*
1054
1059
1175*
1214*
Ang 1
activates Tie-2 (Tie-1)
interacts with integrins
Ang 2
generally ANTAGONIST of Ang 1
Ang1 KO
embryonic lethal
Angiopoietin/Tie regulates
migration
cell-cell adhesion
Ang 1
promotes EC quiescence of EC
stable vessels
involved in maturation step of AG
Ang 2
upregulated in response to HIF VEGF
destabilises blood vessels at the start of AG
TC selection

VE cadherin ->
____ -> matrix remodeling
VEGFR2, _____ _____ ____ _____ -> TC formation
_____ -> pericyte detachment
VEGF -> Permeability, vasodialation, extravasation
loosening junctions
MMPs
TC formation
ANG 2
VEGF
high VEGFR2 levels
low notch signalling
in TC
low VEGFR2 levels
high notch signalling
in SC
Lumen formation
VE cadherin, CD34, sialomucins, VEGF

-vely charged glycoproteins & cytoskeleton retraction
myeloid cell recruitment
ANG2 ,SDF-1alpha, PlGF

for anastamosis
TC guidence & adhesion
semaphorins, ephrins, integrins
Maturation and stabilisation
vascular maintenance - VEGF, ANG1, FGFs, NOTCH

barrier formation -VE - cadherin, ANG-1

PC maturation - PDGF-B, PDGFR-beta, ephrin-B2, ANG1 etc

Basement membrane deposition - TIMP, PAI-1
Soluble VEGF
vessel enlargement
Matrix-bound VEGF
branching
paracrine VEGF (tumours)
branching -> abnormal vessel formation
autocrine
vascular homeostasis
Type I AG inhibitors
inhibit VEGF

Avastin (Ab)
VEGF trap
Type II AG inhibitors
inhibit >1 component

Sutent - VEGFR2 PDGFR cKITR
Tarcevia - VEGF, bFGF, TGFalpha
Type III AG inhibitors
broad range

Endostatin
Caplostatin
Anti-VEGF therapies
weak clinical benefits in cancers due to adaptive resistance

sometimes initial benefit
Avastin
in phase II clinical trials

reduced tumour blood flow and vessel permeability
vessel normalisation could...
help supply anti cancer drugs
Evasion of anti-angiogenic therapy
other pro-AG factor substitution (FGFs, Ang, Ephrins)

Vasculogenesis (EPC-EC)
Vascular mimicry
Tumour cell-EC

Increased PC coverage

Increased tumour cell invasiveness
Side effects of anti VEGF/R therapy
thrombosis
hypertension
microvascular pruning in healthy tissue
interruption of pregnancy
anti PlGF therapy
inhibit growth of VEGFR inhibitor resistant tumours
DOES NOT AFFECT HEALTHY VESSELS

decrease tumour AG
increase EC apoptosis

DOES NOT induce angiogenic gene expression (unlike anti VEGF2)
Collagen XVIII and Perlecan
simulate angiogenic signalling via HS chains

Proteolytic cleavage of C-termini --> release of anti-AG fragments
Endostatin
C-terminal fragment of Collagen XVIII
Endorepellin
C-terminal fragment of Perlecan
Angiostatin
fragment of plasminogen

inhibits plaque neovascularisation and macrophage accumulation
---->
inhibits atherosclerosis
inhibiting PDGFRbeta
decrease PC -> increased EC apoptosis

destabalize vessels

may INCREASE METASTASIS
Pro-angiogenic therapy
gene therapy (VEGF, FGF-2...)

protein therapy (VEGF, FGF-2...)

Cell therapy (EPCs, MSCs...)

combination of 1 & 2
VEGF gene therapy --->
ANGIOMAGENESIS

leaky, fragile capillary labyrinth