Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects
(2015) Journal of Clinical Investigation — Vol. 125, n° 9, p. 3491-3504 (2015)
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- Abstract
- Venous malformations (VMs) 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 these lesions. VMs cause deformity, pain, and local intravascular coagulopathy, and they expand with time. Targeted pharmacological therapies are not available for this condition. Here, we generated a model of VMs by injecting HUVECs expressing the most frequent VM-causing TIE2 mutation, TIE2-L914F, into immune-deficient mice. TIE2-L914F–expressing HUVECs formed VMs with ectatic blood-filled channels that enlarged over time. We tested both rapamycin and a TIE2 tyrosine kinase inhibitor (TIE2-TKI) for their effects on murine VM expansion and for their ability to inhibit mutant TIE2 signaling. Rapamycin prevented VM growth, while TIE2-TKI had no effect. In cultured TIE2-L914F–expressing HUVECs, rapamycin effectively reduced mutant TIE2-induced AKT signaling and, though TIE2-TKI did target the WT receptor, it only weakly suppressed mutant-induced AKT signaling. In a prospective clinical pilot study, we analyzed the effects of rapamycin in 6 patients with difficult–to-treat venous anomalies. Rapamycin reduced pain, bleeding, lesion size, functional and esthetic impairment, and intravascular coagulopathy. This study provides a VM model that allows evaluation of potential therapeutic strategies and demonstrates that rapamycin provides clinical improvement in patients with venous malformation.
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Boscolo, E., Limaye, N., Huang, L., Kang, K.-T., Soblet, J., Uebelhoer, M., Mendola, A., Natynki, M., Seront, E., Dupont, S., Hammer, J., Legrand, C., Brugnara, C., Eklund, L., Vikkula, M., Bischoff, J., & Boon, L. (2015). Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. Journal of Clinical Investigation, 125(9), 3491-3504. https://doi.org/10.1172/JCI76004 (Original work published 2015)