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

J Clin Invest. 2015 Sep;125(9):3491-504. doi: 10.1172/JCI76004. Epub 2015 Aug 10.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Disease Models, Animal
  • Female
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Immunosuppressive Agents / administration & dosage*
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Mutation, Missense*
  • Pilot Projects
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, TIE-2* / genetics
  • Receptor, TIE-2* / metabolism
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • Sirolimus / administration & dosage*
  • Vascular Malformations* / drug therapy
  • Vascular Malformations* / genetics
  • Vascular Malformations* / metabolism
  • Vascular Malformations* / pathology
  • Veins

Substances

  • Immunosuppressive Agents
  • Receptor, TIE-2
  • Tek protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Sirolimus