Essay: Angiogenesis, molecular and cellular mechanisms Flashcards Preview

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Flashcards in Essay: Angiogenesis, molecular and cellular mechanisms Deck (24):
1

Angiogenesis

- The process of forming new blood vessels from existing ones

- Also the widening of existing blood vessels to increase flow

2

Vasculogenesis

- Formation of blood vessels in the embryo

- in situ differentiation of progenitor cells into ECs

- ECs assemble into vascular labyrinth

3

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

4

Permeability

- Fenestration

- PECAM and VE-cadherin reorganisation

- Src kinase involvement

5

Tie2 role and inhibition

- Opposes permeability

- Tightens intra-endothelial connections

- Activated by angiopoietin 1 (stabilises vasculature)

- Inhibited by angiopoietin 2

6

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

7

Proteinase families in angiogenesis

- Plasminogen activators

- Matrix metalloproteinases

- Chymases

- Heparases

8

Proteinase role

- Degrade matrix molecules

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

9

u-PA

Urokinase-type plasminogen activator

- Essential for revscularisation after MI

- Inhibiting it stops tumour angiogenesis

10

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

11

VEGFR 1,2,3

VEGFR1:
Releases extracellular domain to bind, inhibit VEGF

VEGFR2:
Main blood vessel VEGFR

VEGFR3:
Important in lymphatic vasculature

12

Tip Cell motility

- Actin remodelling

- Rac1, RhoA and Cdc42

13

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

14

Sprouting

- Tip cells sprout towards the VEGF gradient,

- Adjacent stalk cells follow the guiding tip cell

- Proliferate to support sprout elongation

15

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

16

Expression changes in stalk cells

Reduced tip cell-enriched genes:

- UNC5B
- PDGFB

Increased VEGFR1 (decoy)

17

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

18

Lumen formation: 3 mechanisms

1. Intracellular vacuole coalescence

2. Intercellular vacuole exocytosis

3. Luminal repulsion

19

Intracellular vacuole coalescence

- Vacuoles form within each stalk cell

- Connect with each other

- Connect with vacuoles from neighbouring cells

20

Intercellular vacuole exocytosis

- Vacuoles are exocytosed from stalk cells

- Lumen formed in intercellular space

21

Luminal Repulsion

- VE-cadherin establishes apical/basal gradient

- CD34 recruited (negatively charge)

- Electrical repulsion between apical membrane of adjacent cells creates lumen

22

Anastomosis- Macrophage interactions

- Resident macrophages can promote contact of filopodia from meeting tip cells

- May use Tie2, notch or CXC34 pathways

23

VE-cadherin in anastomosis

- Contacting filopodia form junctions using VE-cadherin

- Junctions then form along cell interface

24

Vessel Stabalisation

- 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