Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects
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...
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| Published in: | The Journal of clinical investigation Vol. 125; no. 9; pp. 3491 - 3504 |
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| Main Authors: | , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
American Society for Clinical Investigation
01.09.2015
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| Subjects: | |
| ISSN: | 0021-9738, 1558-8238 |
| Online Access: | Get full text |
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| 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. |
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| AbstractList | 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. |
| Audience | Academic |
| Author | Hammer, Jennifer Legrand, Catherine Boon, Laurence M. Uebelhoer, Melanie Seront, Emmanuel Boscolo, Elisa Vikkula, Miikka Bischoff, Joyce Limaye, Nisha Kang, Kyu-Tae Huang, Lan Dupont, Sophie Mendola, Antonella Eklund, Lauri Soblet, Julie Natynki, Marjut Brugnara, Carlo |
| AuthorAffiliation | 2 Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium 5 Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint Luc, Université catholique de Louvain, Brussels, Belgium 6 Institute of Statistics, Biostatistics, and Actuarial Sciences, Université catholique de Louvain, Louvain-la-Neuve, Belgium 4 Centre du Cancer, Department of Pediatric Oncology, and 3 Oulu Center for Cell-Matrix Research, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland 1 Vascular Biology Program and Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA 7 Department of Laboratory Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA |
| AuthorAffiliation_xml | – name: 4 Centre du Cancer, Department of Pediatric Oncology, and – name: 7 Department of Laboratory Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA – name: 2 Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium – name: 6 Institute of Statistics, Biostatistics, and Actuarial Sciences, Université catholique de Louvain, Louvain-la-Neuve, Belgium – name: 5 Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint Luc, Université catholique de Louvain, Brussels, Belgium – name: 1 Vascular Biology Program and Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA – name: 3 Oulu Center for Cell-Matrix Research, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland |
| Author_xml | – sequence: 1 givenname: Elisa surname: Boscolo fullname: Boscolo, Elisa – sequence: 2 givenname: Nisha surname: Limaye fullname: Limaye, Nisha – sequence: 3 givenname: Lan surname: Huang fullname: Huang, Lan – sequence: 4 givenname: Kyu-Tae surname: Kang fullname: Kang, Kyu-Tae – sequence: 5 givenname: Julie surname: Soblet fullname: Soblet, Julie – sequence: 6 givenname: Melanie surname: Uebelhoer fullname: Uebelhoer, Melanie – sequence: 7 givenname: Antonella surname: Mendola fullname: Mendola, Antonella – sequence: 8 givenname: Marjut surname: Natynki fullname: Natynki, Marjut – sequence: 9 givenname: Emmanuel surname: Seront fullname: Seront, Emmanuel – sequence: 10 givenname: Sophie surname: Dupont fullname: Dupont, Sophie – sequence: 11 givenname: Jennifer surname: Hammer fullname: Hammer, Jennifer – sequence: 12 givenname: Catherine surname: Legrand fullname: Legrand, Catherine – sequence: 13 givenname: Carlo surname: Brugnara fullname: Brugnara, Carlo – sequence: 14 givenname: Lauri surname: Eklund fullname: Eklund, Lauri – sequence: 15 givenname: Miikka surname: Vikkula fullname: Vikkula, Miikka – sequence: 16 givenname: Joyce surname: Bischoff fullname: Bischoff, Joyce – sequence: 17 givenname: Laurence M. surname: Boon fullname: Boon, Laurence M. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26258417$$D View this record in MEDLINE/PubMed |
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| Copyright | COPYRIGHT 2015 American Society for Clinical Investigation Copyright American Society for Clinical Investigation Sep 2015 Copyright © 2015, American Society for Clinical Investigation 2015 American Society for Clinical Investigation |
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| SubjectTerms | 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 |
| Title | Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects |
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