Venous malformations (VMs) are vascular anomalies characterized by dilated and malformed veins that can result in chronic and painful swelling, bleeding, and deformity. Mutations in the gene encoding the tyrosine kinase receptor TIE2, which is critical for proper angiogenesis, underlie both inherited and spontaneous forms of VM, with the somatic TIE2-L914F mutation accounting for the majority of sporadic lesions. Currently, therapeutic options to reduce VM severity or alleviate symptoms are lacking. Elisa Boscolo and colleagues Harvard Medical School developed a murine model of TIE2-L914F-associted VM and used this model to identify potential therapeutic strategies. Expression of TIE2-L914F in human umbilical vein endothelial cells (HUVECs) increased TIE2 activation and phosphorylation of the downstream target AKT. TIE2-L914F-expressing HUVECs injected into immune-deficient mice formed VMs with ectatic vessels. These TIE2-L914F lesions enlarged over time and exhibited hampered blood flow due to formation of non-pulsatile veins—phenotypes comparable to patient VMs. Treatment of cultured TIE2-L914F HUVECs with TIE2 tyrosine kinase inhibitor (TIE2-TKI) or rapamycin reduced TIE2 induction of AKT signaling; however, TIE2-TKI inhibition of TIE2-L914F was markedly weaker than rapamycin. Moreover, rapamycin treatment halted VM growth in mice with established TIE2-L914F lesions. In a prospective clinical trial of patients with refractory VMs, rapamycin treatment reduced VM volume, bleeding, and pain. This study provides a model to test potential therapeutic strategies for VM and suggest rapamycin should be further explored as an effective targeted molecular therapy for VM. The accompanying image shows explants taken from mice 7 days after injection of WT TIE2-expressing HUVECs (left) or TIE2-L914F-expressing HUVECs (right) stained for venous endothelium (UEA1, red). Endothelial nuclei stained blue with DAPI. Note the formation of ectatic blood vessels in TIE2-L914F explants.
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.
Elisa Boscolo, Nisha Limaye, Lan Huang, Kyu-Tae Kang, Julie Soblet, Melanie Uebelhoer, Antonella Mendola, Marjut Natynki, Emmanuel Seront, Sophie Dupont, Jennifer Hammer, Catherine Legrand, Carlo Brugnara, Lauri Eklund, Miikka Vikkula, Joyce Bischoff, Laurence M. Boon