Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects

• Published in: The Journal of clinical investigation Vol. 125; no. 9; pp. 3491 - 3504
• Main Authors: Boscolo, Elisa, Limaye, Nisha, Huang, Lan, Kang, Kyu-Tae, Soblet, Julie, Uebelhoer, Melanie, Mendola, Antonella, Natynki, Marjut, Seront, Emmanuel, Dupont, Sophie, Hammer, Jennifer, Legrand, Catherine, Brugnara, Carlo, Eklund, Lauri, Vikkula, Miikka, Bischoff, Joyce, Boon, Laurence M.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2015
• Subjects: Adolescent; Adult; Analysis; Animal models in research; Animals; Biomedical research; Disease Models, Animal; Drug therapy; Female; Genetic aspects; Health aspects; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Humans; Immunosuppressive Agents - administration & dosage; Male; Mice; Mice, Nude; Middle Aged; Mutation; Mutation, Missense; Patients; Phosphorylation; Pilot Projects; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Receptor, TIE-2 - genetics; Receptor, TIE-2 - metabolism; Risk factors; Signal Transduction - drug effects; Signal Transduction - genetics; Sirolimus - administration & dosage; Vascular Malformations - drug therapy; Vascular Malformations - genetics; Vascular Malformations - metabolism; Vascular Malformations - pathology; Veins; Venous insufficiency; Belgium
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI76004

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.