The VEGFs and angiopoietins are the only known growth factor families specific for vascular endothelial cells, though individual ephrins also have selective actions on blood vessels. Emerging data indicate that VEGF and the angiopoietins work in complementary and co-ordinated fashion during normal vascular development. While VEGF is required for the initiation of vessel formation, Angiopoietin-1 seems critical during subsequent vessel maturation and stabilization. While vessels formed in the presence of excess VEGF are leaky and fragile (and associated with tissue oedema and haemorrhage), vessels made in the presence of excess Angiopoietin-1 are actually resistant to vascular leak induced by VEGF or inflammatory mediators. Correcting an imbalance towards excess VEGF seen in many pathological states, by either blocking the excess VEGF or administering additional Angiopoietin-1, could decrease plasma leakage and the resulting oedema, and thus have important clinical benefit in numerous disease settings. Data will be shown regarding the impact of inducing angiogenesis using VEGF alone, Angiopoietin-1 alone, or the combination.
Recent gene knockout studies suggest that Angiopoietin-2 plays a key role within the vessel wall, in regulating vessel destabilization and vessel regressions, and in regulating development of lymphatics. Interestingly, recent work with EphrinB2 also suggests a key role in vessel wall formation, particularly for arterial vessels.
Re-examination of tumour angiogenesis, in the context of considering the roles of these various factors, has led to a new view of how tumours interact with the vasculature. In contrast to prevailing dogma suggesting that tumours arise as avascular masses that require new angiogenesis for their initial vasculaturization and further growth, we suggest that tumours can instead grow by co-opting existing vessels. Indeed, blocking tumour angiogenesis by using a potent ‘VEGF Trap’ reveals that tumours can clearly grow invasively by vessel co-option in the absence of angiogenesis. In addition to regulating vessel formation and survival, the balance between VEGF and angiopoietins seems to regulate the function and quality of tumour vessels, e.g. tumour vessels are often subject to excess VEGF and are thus leaky and fragile (and associated with tissue oedema and haemorrhage), due to relative lack of the vessel stabilization, maturation and anti-permeability functions provided by Angiopoietin-1. In addition, Angiopoietin-2 and EphrinB2 are dramatically induced in tumour vessels, providing perhaps the best early markers of co-opted or angiogenic tumour vessels, and thus targets of anti-angiogenesis approaches. The discovery and characterization of multiple new angiogenesis regulatory factors is beginning to lead to a new understanding of the molecular basis of blood vessel development that seems likely to have important therapeutic implications.