title: Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects.
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.
authors.forename: Elisa
authors.initials: E
authors.lastname: Boscolo
authors.forename: Nisha
authors.initials: N
authors.lastname: Limaye
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Kang
authors.forename: Julie
authors.initials: J
authors.lastname: Soblet
authors.forename: Melanie
authors.initials: M
authors.lastname: Uebelhoer
authors.forename: Antonella
authors.initials: A
authors.lastname: Mendola
authors.forename: Marjut
authors.initials: M
authors.lastname: Natynki
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Seront
authors.forename: Sophie
authors.initials: S
authors.lastname: Dupont
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hammer
authors.forename: Catherine
authors.initials: C
authors.lastname: Legrand
authors.forename: Carlo
authors.initials: C
authors.lastname: Brugnara
authors.forename: Lauri
authors.initials: L
authors.lastname: Eklund
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
authors.forename: Joyce
authors.initials: J
authors.lastname: Bischoff
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Boon
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D020125:Mutation, Missense; D010865:Pilot Projects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000008:administration & dosage*; D054079:Vascular Malformations / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014680:Veins
chemical_list: D007166:Immunosuppressive Agents; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus