TIE2 inhibition has been tested in

TIE2 inhibition has been tested in a mouse transplantation model of VM, but likely due to poor inhibition efficiency of the TIE2-TKI used, the results were only modest . In postnatal and adult mice, TIE2 seems to have only a limited role in overall vascular homeostasis, as conditional knockout after birth leads to defects that seem to be mainly limited to Schlemm’s canal of the eye, lymphatic capillaries of the corneal limbus and postnatal mouse retina . Inhibition of the mutated TIE2 in VMs could thus be possible without severly disrupting normal vascular functions. TIE2 inhibitors currently in pre-clinical and clinical trials are multikinase inhibitors targeting additional kinases such as PDGFRb, VEGFR and MAPKs . Even though the inhibition of multiple targets in general would appear undesirable, the targeting of TIE2 and MAPKs signalling in combination could be beneficial in VMs, as Erk1/2-mediated signalling causes part of the TIE2 mutation-induced cellular dysfunctions in in vitro studies . Perhaps the most significant limitation of targeting TIE2 is that it would likely be of no use in VMs caused by mutations in PIK3CA or other genes downstream of TIE2. In addition, TIE2 inhibition cannot be generalized to other vascular anomalies as TIE2 gain-of-function mutations have thus far only been found in VMs.