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59 Cards in this Set
- Front
- Back
Angiogenesis
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formation of new blood vessels from an existing vascular bed
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Too much AG -->
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cancer
diabetes atherosclerosis psoriasis |
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Too little AG -->
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baldness
ischemic heart disease stroke blood clots limb fractures |
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Mechanism overview
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Tip Cell selection
Tip Cell navigation Stalk cell elongation - lumen morphogenesis Anastamosis (of 2 TC) Maturation & stabilisation |
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in vitro models
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EC on:
23 substrata + VEGF matrigel |
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in vivo models
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CAM assay
zebrafish cornea assay etc |
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AG activators
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VEGF, PLGF, VEGFR
Ang 1 & Tie 2 PDGF - BB and Rs FGF, HGF TGFbeta1, endoglin TGFbeta Ephrins MMPs, heparanase NOS, cyclooxygenase Integrins |
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AG Inhibitors
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VEGFR1, sVEGFR1, neurophillin
Angiopoietin 2 TSP-1, TSP-2 Angiostatin Endostatin Restin TIMPs, MMP Is Maspin |
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mice with EC deletion of Dicer
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defective postnatal AG
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pro-angiomiRs
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promote AG via targeting negative regulators
e.g miR-126 vis versa |
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Hypoxia activates ______ which activates _______ __ __________ ______
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HIF
trx of pro-angiogenic factors (VEGF) |
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KO VEGF/VEGFR
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no EC
embryonic lethal Haploinsufficiency |
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KO VEGFR1
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Excess EC
no tube/vessel formed |
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KO ANG1/TIE2
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No Pericytes
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VEGF
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homodimeric glycoprotein
VEGF-A (main one) - splice varients VEGF, B, C, D PlGF diff species bind to different Rs with diff AFFINITES |
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VEGFR
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1
2 3 Neuropilin 1 & 2 *not EC specific* oooooooooo |
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'b' variants of VEGFA
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ANTI-ANGIOGENIC
differ by 6aa @ C terminal - affects ability to bind Rs |
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VEGF A function
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Vasculogenesis
ANGIOGENESIS |
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VEGF B function
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Coronary vascularisation and growth
KO-> smaller heart |
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VEGF C function
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lymphatic development
activates TC |
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PlGF function
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Vascular remodelling in ADULTS and disease
not necessary for development! |
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Predominant isoforms of VEGF A
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165 (has heparin binding domain -> matrix)
121 (freely diffusible) |
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VEGFR 1
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vascular development
haematopoietic cell recruitment to new blood vessels decoy receptor |
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*VEGFR 2
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vasculogenesis & angiogenesis
EC permeability, migration, proliferation, differentiation TC SELECTION |
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VEGFR 3
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lymphanogenesis
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autophosphorylation Tyr sites on VEGFR2
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951*
1054 1059 1175* 1214* |
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Ang 1
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activates Tie-2 (Tie-1)
interacts with integrins |
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Ang 2
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generally ANTAGONIST of Ang 1
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Ang1 KO
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embryonic lethal
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Angiopoietin/Tie regulates
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migration
cell-cell adhesion |
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Ang 1
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promotes EC quiescence of EC
stable vessels involved in maturation step of AG |
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Ang 2
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upregulated in response to HIF VEGF
destabilises blood vessels at the start of AG |
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TC selection
VE cadherin -> ____ -> matrix remodeling VEGFR2, _____ _____ ____ _____ -> TC formation _____ -> pericyte detachment VEGF -> Permeability, vasodialation, extravasation |
loosening junctions
MMPs TC formation ANG 2 VEGF |
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high VEGFR2 levels
low notch signalling |
in TC
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low VEGFR2 levels
high notch signalling |
in SC
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Lumen formation
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VE cadherin, CD34, sialomucins, VEGF
-vely charged glycoproteins & cytoskeleton retraction |
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myeloid cell recruitment
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ANG2 ,SDF-1alpha, PlGF
for anastamosis |
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TC guidence & adhesion
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semaphorins, ephrins, integrins
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Maturation and stabilisation
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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 |
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Soluble VEGF
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vessel enlargement
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Matrix-bound VEGF
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branching
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paracrine VEGF (tumours)
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branching -> abnormal vessel formation
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autocrine
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vascular homeostasis
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Type I AG inhibitors
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inhibit VEGF
Avastin (Ab) VEGF trap |
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Type II AG inhibitors
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inhibit >1 component
Sutent - VEGFR2 PDGFR cKITR Tarcevia - VEGF, bFGF, TGFalpha |
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Type III AG inhibitors
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broad range
Endostatin Caplostatin |
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Anti-VEGF therapies
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weak clinical benefits in cancers due to adaptive resistance
sometimes initial benefit |
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Avastin
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in phase II clinical trials
reduced tumour blood flow and vessel permeability |
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vessel normalisation could...
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help supply anti cancer drugs
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Evasion of anti-angiogenic therapy
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other pro-AG factor substitution (FGFs, Ang, Ephrins)
Vasculogenesis (EPC-EC) Vascular mimicry Tumour cell-EC Increased PC coverage Increased tumour cell invasiveness |
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Side effects of anti VEGF/R therapy
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thrombosis
hypertension microvascular pruning in healthy tissue interruption of pregnancy |
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anti PlGF therapy
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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) |
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Collagen XVIII and Perlecan
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simulate angiogenic signalling via HS chains
Proteolytic cleavage of C-termini --> release of anti-AG fragments |
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Endostatin
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C-terminal fragment of Collagen XVIII
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Endorepellin
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C-terminal fragment of Perlecan
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Angiostatin
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fragment of plasminogen
inhibits plaque neovascularisation and macrophage accumulation ----> inhibits atherosclerosis |
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inhibiting PDGFRbeta
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decrease PC -> increased EC apoptosis
destabalize vessels may INCREASE METASTASIS |
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Pro-angiogenic therapy
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gene therapy (VEGF, FGF-2...)
protein therapy (VEGF, FGF-2...) Cell therapy (EPCs, MSCs...) combination of 1 & 2 |
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VEGF gene therapy --->
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ANGIOMAGENESIS
leaky, fragile capillary labyrinth |