Venous Malformation: from causative TIE2 mutations to murine model and targeted therapy. TIE2 mutations in VM

Background: Venous malformations (VM) are composed of ectatic veins with scarce smooth muscle cell coverage. Activating mutations in the endothelial cell tyrosine kinase receptor TIE2 are a common cause of the lesions. VMs expand causing deformity, pain, and local intravascular coagulopathy. Despite sclerotherapy or excision, lesions often recur. Targeted pharmacological therapies are not available. Methods: To generate a model of VM, we injected, in mouse, human umbilical vein endothelial cells (HUVECs) expressing TIE2-L914F, the most frequent VM-causative TIE2 mutation. We tested rapamycin and a TIE2 tyrosine kinase inhibitor (TIE2-TKI), in vivo, for effects on murine VM expansion, and in vitro, for the ability to inhibit mutant-TIE2 signaling. A prospective clinical pilot study analyzed the effects of rapamycin in six patients with difficult–to-treat venous anomalies. Results: HUVECs expressing TIE2-L914F formed VMs with ectatic blood-filled channels. In this VM model, rapamycin prevented lesion growth and, in vitro, effectively reduced mutant-TIE2-induced AKT signaling. TIE2-TKI, developed to target the wildtype receptor, displayed weaker suppression of TIE2 and AKT signaling in HUVECTIE2-L914F. In patients, rapamycin treatment reduced pain, bleeding, lesion size, functional and esthetic impairment, and intravascular coagulopathy. Conclusions: Endothelial cells with TIE2-L914F recapitulated VM in mice. Rapamycin halted lesion expansion by targeting activated AKT signaling downstream of the mutant-TIE2. In patients with difficult-to-treat VMs, rapamycin induced important clinical improvement.