Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 9, Pages 3491-3504Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI76004
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Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [P01 AR048564]
- National Heart, Lung, and Blood Institute [R01 HL117952]
- Manton Center for Orphan Disease
- Charles H. Hood Foundation
- Belgian Science Policy Office Interuniversity Attraction Poles (BELSPO-IAP) Programme [IAP P7/43-BeMGI]
- F.R.S.-FNRS [T.0026.14]
- Academy of Finland [136880]
- Televie, Belgium
- la Communaute Francaise de Wallonie-Bruxelles
- la Lotterie Nationale, Belgium
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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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