Angiogenesis

1. Hypoxia

Hypoxia induces HIF-1 expression and the consequent release of pro-angiogenic factors, of which VEGF is the most important

2. Proteolytic degradation

Hypoxia also upregulates protease expression, leading to basement membrane degradation and pericyte detachment

3. Tip cell migration

Specialized endothelial cells - ‘tip cells’ - migrate along angiogenic factor gradient

4. Tube formation

Endothelial cells are differentiated into highly proliferative stalk cells which make up the main body of the new vessel

5. Regulation of vessel size

VEGF stimulates DLL4 secration which binds to Notch-1 receptors; this down regulates VEGFR suppressing proliferation

6. Tumor vascularization

PDGF beta stimulates pericyte attachment and reduces proliferation and VEGF sensitivity. Blood supply stimulates further tumor growth