Essay: Angiogenesis, molecular and cellular mechanisms Flashcards
Angiogenesis
- The process of forming new blood vessels from existing ones
- Also the widening of existing blood vessels to increase flow
Vasculogenesis
- Formation of blood vessels in the embryo
- in situ differentiation of progenitor cells into ECs
- ECs assemble into vascular labyrinth
Vasodilatation, endothelial permeability control and peri-endothelial support
- NO causes vasodilatation
- VEGF makes the vessel wall become more permeable
- Extravasated plasma proteins form provisional scaffold for migrating ECs
Permeability
- Fenestration
- PECAM and VE-cadherin reorganisation
- Src kinase involvement
Tie2 role and inhibition
- Opposes permeability
- Tightens intra-endothelial connections
- Activated by angiopoietin 1 (stabilises vasculature)
- Inhibited by angiopoietin 2
Destabilisation of existing vasculature
For existing ECs to migrate and form new vessels, they must:
- Loosen intra-endothlial connections
- Relieve peri-endothelial support
Done by:
- Tie2-R antagonism with angiopoietin 2
Proteinase families in angiogenesis
- Plasminogen activators
- Matrix metalloproteinases
- Chymases
- Heparases
Proteinase role
- Degrade matrix molecules
- Activate/liberate GFs sequestered in ECM
bFGF, VEGF and IGF-1
u-PA
Urokinase-type plasminogen activator
- Essential for revscularisation after MI
- Inhibiting it stops tumour angiogenesis
HIFs
- Hypoxia inducible factors
- Can activate GFs in hypoxia
- In normoxia, HIFs are ubiquitinised by PHD2 and PHD3*
- Undergo proteolytic degradation
- prolyl hydroxylase domain containing proteins
VEGFR 1,2,3
VEGFR1:
Releases extracellular domain to bind, inhibit VEGF
VEGFR2:
Main blood vessel VEGFR
VEGFR3:
Important in lymphatic vasculature
Tip Cell motility
- Actin remodelling
- Rac1, RhoA and Cdc42
Tip cell selection
- VEGF signal from the hypoxic region
- CG established
2 Neighbouring cells
- Both signalling with DLL4-notch to each other
- VEGF/notch-dependent regulatory mechanism
- Tip cell inhibits neighbour tip-formation
Sprouting
- Tip cells sprout towards the VEGF gradient,
- Adjacent stalk cells follow the guiding tip cell
- Proliferate to support sprout elongation
Notch in stalk cells
- Tip cell secretes DLL4
- Suppresses VEGFR2 and DLL4 expression in stalk cells
- Less sensitive to VEGF
- Less able to activate notch signalling in adjacent cells
Expression changes in stalk cells
Reduced tip cell-enriched genes:
- UNC5B
- PDGFB
Increased VEGFR1 (decoy)
Jagged-1 signalling to tip cell
- Selectively expressed in stalk cells
- Competes with DLL4 to bind notch in tip cell
- Jagged-1 binding inhibits notch signalling
Lumen formation: 3 mechanisms
- Intracellular vacuole coalescence
- Intercellular vacuole exocytosis
- Luminal repulsion
Intracellular vacuole coalescence
- Vacuoles form within each stalk cell
- Connect with each other
- Connect with vacuoles from neighbouring cells
Intercellular vacuole exocytosis
- Vacuoles are exocytosed from stalk cells
- Lumen formed in intercellular space
Luminal Repulsion
- VE-cadherin establishes apical/basal gradient
- CD34 recruited (negatively charge)
- Electrical repulsion between apical membrane of adjacent cells creates lumen
Anastomosis- Macrophage interactions
- Resident macrophages can promote contact of filopodia from meeting tip cells
- May use Tie2, notch or CXC34 pathways
VE-cadherin in anastomosis
- Contacting filopodia form junctions using VE-cadherin
- Junctions then form along cell interface
Vessel Stabalisation
- Pericytes recruited
- TIMP3 and angiopoietin 1 signalling
- Ang1 activates Tie2
DLL4-notch signalling
- Decreases VEGFR2 to prevent sprouting
- Induces NRARP -> Wnt -> tight junction formation
