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Module 3 > Essay: Angiogenesis, molecular and cellular mechanisms > Flashcards

Essay: Angiogenesis, molecular and cellular mechanisms Flashcards

1
Q

Angiogenesis

A
  • The process of forming new blood vessels from existing ones
  • Also the widening of existing blood vessels to increase flow
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2
Q

Vasculogenesis

A
  • Formation of blood vessels in the embryo
  • in situ differentiation of progenitor cells into ECs
  • ECs assemble into vascular labyrinth
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3
Q

Vasodilatation, endothelial permeability control and peri-endothelial support

A
  • NO causes vasodilatation
  • VEGF makes the vessel wall become more permeable
  • Extravasated plasma proteins form provisional scaffold for migrating ECs
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4
Q

Permeability

A
  • Fenestration
  • PECAM and VE-cadherin reorganisation
  • Src kinase involvement
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5
Q

Tie2 role and inhibition

A
  • Opposes permeability
  • Tightens intra-endothelial connections
  • Activated by angiopoietin 1 (stabilises vasculature)
  • Inhibited by angiopoietin 2
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6
Q

Destabilisation of existing vasculature

A

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
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7
Q

Proteinase families in angiogenesis

A
  • Plasminogen activators
  • Matrix metalloproteinases
  • Chymases
  • Heparases
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8
Q

Proteinase role

A
  • Degrade matrix molecules

- Activate/liberate GFs sequestered in ECM
bFGF, VEGF and IGF-1

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9
Q

u-PA

A

Urokinase-type plasminogen activator

  • Essential for revscularisation after MI
  • Inhibiting it stops tumour angiogenesis
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10
Q

HIFs

A
  • 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
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11
Q

VEGFR 1,2,3

A

VEGFR1:
Releases extracellular domain to bind, inhibit VEGF

VEGFR2:
Main blood vessel VEGFR

VEGFR3:
Important in lymphatic vasculature

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12
Q

Tip Cell motility

A
  • Actin remodelling

- Rac1, RhoA and Cdc42

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13
Q

Tip cell selection

A
  • 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
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14
Q

Sprouting

A
  • Tip cells sprout towards the VEGF gradient,
  • Adjacent stalk cells follow the guiding tip cell
  • Proliferate to support sprout elongation
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15
Q

Notch in stalk cells

A
  • 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
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16
Q

Expression changes in stalk cells

A

Reduced tip cell-enriched genes:

  • UNC5B
  • PDGFB

Increased VEGFR1 (decoy)

17
Q

Jagged-1 signalling to tip cell

A
  • Selectively expressed in stalk cells
  • Competes with DLL4 to bind notch in tip cell
  • Jagged-1 binding inhibits notch signalling
18
Q

Lumen formation: 3 mechanisms

A
  1. Intracellular vacuole coalescence
  2. Intercellular vacuole exocytosis
  3. Luminal repulsion
19
Q

Intracellular vacuole coalescence

A
  • Vacuoles form within each stalk cell
  • Connect with each other
  • Connect with vacuoles from neighbouring cells
20
Q

Intercellular vacuole exocytosis

A
  • Vacuoles are exocytosed from stalk cells

- Lumen formed in intercellular space

21
Q

Luminal Repulsion

A
  • VE-cadherin establishes apical/basal gradient
  • CD34 recruited (negatively charge)
  • Electrical repulsion between apical membrane of adjacent cells creates lumen
22
Q

Anastomosis- Macrophage interactions

A
  • Resident macrophages can promote contact of filopodia from meeting tip cells
  • May use Tie2, notch or CXC34 pathways
23
Q

VE-cadherin in anastomosis

A
  • Contacting filopodia form junctions using VE-cadherin

- Junctions then form along cell interface

24
Q

Vessel Stabalisation

A
  • Pericytes recruited
  • TIMP3 and angiopoietin 1 signalling
  • Ang1 activates Tie2

DLL4-notch signalling

  1. Decreases VEGFR2 to prevent sprouting
  2. Induces NRARP -> Wnt -> tight junction formation

Module 3 (16 decks)

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