Angiogenesis

Question 1

What is vasculogenesis?

Answer 1

EMBRYO-The differentiation of precursor cells (angioblasts) into endothelial cells during embryogenesis

Question 2

What is angiogenesis?

Answer 2

*formation of vascular sprouts from pre existing vessels
*forms highly branched vascular plexus
*primary plexus remodelled several times until mature system of vessels with different diameters formed
*BOTH embryo and postnatal

Question 3

When does angiogenesis occur?

Answer 3

*reproduction
*during wound healing

Question 4

What are examples of pro angiongenic factors?

Answer 4

*VEGF’s- vascular endothelial growth factor
* angiopoietin 1
*FGF-2- fibroblast growth factor
*PDGF- platelet derived growth factor

ALL regulated by tyrosine kinase inhibitors

Question 5

What conditions does unregulated angiogenesis cause?

Answer 5

*loss of vision- degenerative retinal diseases
*cancer

Question 6

Why is cancer an angiogenesis-dependent process ?

Answer 6

Tumour needs extensive vascular network to supply oxygen and nutrients
To provide a way for tumour cells to enter circulation and metastasise to distant organs

Question 7

What is the angiogenesis cascade?

Answer 7

1. Pro angiogenic factor produced- VEGF
2. Pro angiogenic factors bind to endothelial cell receptors
3. Endothelial cells activated- release proteases which degrade basement membrane surrounding existing vessel
4. Endothelial cell proliferation
5. Migration of endothelial cells in interstitial space
6. Extra cellular matrix remodelling
   7.Lumen formed
   8.Fusion of newly formed vessels into loops
   9.New vessels stabilised by generation of new basement membrane by recruiting pericytes

Question 8

What pro angiogenic factor is the main drug target?

Answer 8

VEGF
Tyrosine kinase- intracellular signalling

Question 9

What is the role of VEGF?

Answer 9

*regulates permeability
*loss of single VEGF allele is LETHAL
*transcription of VEGF induced by cytokines

Question 10

What regulates VEGF?

Answer 10

*hypoxic (low o2) UPREGULATES VEGF to increase tissue oxygenation through vessel growth

Question 11

What are the two VEGF receptors on endothelium?

Answer 11

*VEGFR-1
*VEGFR-2
VEGF receptor also upregulated by hypoxia

Question 12

How does basement membrane breakdown occur?

Answer 12

Proteolysis
-break down of underlying basement membrane
-invasion of stroma of surrounding tissue
Both require cooperative activity of
*urokinase-plasminogen activator
*matrix metalloproteinase (MMP) enzyme systems

Question 13

What is the role of the stroma in angiogenesis?

Answer 13

Consists of fibroblastic, inflammatory and immune cells
A source of angiogenic factors

Question 14

What must be inhibited during formation of new basement membrane ?

Answer 14

Proteolysis of basement membrane
Formation of new ECM is done by alternate cycles of activation and inhibition of Proteolysis

Question 15

What are two methods of anti VEGF?

Answer 15

*monoclonal antibodies- against specific pro angiogenic growth factors and or receptors
*small molecule tyrosine kinase inhibitors- against MULTIPLE pro angiogenic growth factor receptors

Question 16

What drugs are examples of anti VEGFs?

Answer 16

*bevacizumab- leaves free plasma VEGF undetectable SE- hypertension
*alfibercept- VEGF trap- decoy receptor to bind VEGF so it can’t bind to norm VEGF-1/2 receptors

Question 17

What are limitations of anti angiogenic therapy?

Answer 17

*doesn’t eradicate tumours as stand alone therapy-combined with chemo
*long treatment of anti angio causes such a reduction in micro vascular density that delivery of chemo affected
*complicated process with many growth factors and cellular processes

Question 18

What are examples of anti VEGF therapy for macular degeneration/diabetic retinopathy?

Answer 18

*Macugen- antagonist. Prevents binding to VEGF receptor
*ranibizumab (lucentis)
*alfibercept- VEGF trap
Injected into eye