In diseases and conditions associated with vascular injury and endothelial dysfunction such as diabetes, hypertension and hypoxia, VE-PTP and Angpt2, factors that decrease Tie2 activity, are upregulated. This results in a significant decrease in Tie2 activation.
Blocking Angpt2 activity, ostensibly to increase Angpt1’s opportunity to activate Tie2, may help to maintain vascular stability.
Our hypothesis, based on our pre-clinical experiments, suggests that removal of Angpt2 may not be the optimal approach to activate the Tie2 receptor. In the complete absence of Angpt2, our scientific results have shown that Tie2 is still deactivated downstream of the angiopoietins by VE-PTP, resulting in an Angpt1-resistant state.
In this state, Angpt1 is not able to maintain Tie2 activity, resulting in a potential loss of blood vessel integrity, which ultimately may lead to vascular inflammation, leakage and pathologic neovascularization.
We believe directly blocking VE-PTP could overcome this Angpt1 resistance and activate the Tie2 receptor. Our pre-clinical experiments suggest this may happen regardless of Angpt1 or Angpt2 levels and may ultimately prove to be the most clinically superior way to manipulate activity of the Tie2 receptor.