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Cited by 20Vascular Malformations and HemangiomasVascular Malformations Diagnosis and TreatmentVascular Anomalies and Treatments

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Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition

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Kapp, Friedrich G., Bazgir, Farhad, Mahammadzade, Nagi, Mehrabipour, Mehrnaz, Vassella, Erik, Bernhard, Sarah M., Döring, Yvonne, Holm, Annegret, Karow, Axel, Seebauer, Caroline, Platz Batista da Silva, Natascha, Wohlgemuth, Walter A., Oppenheimer, Aviv, Kröning, Pia, Niemeyer, Charlotte M., Schanze, Denny, Zenker, Martin, Eng, Whitney, Ahmadian, Mohammad R., Baumgartner, Iris, Rössler, Jochen·2024·Angiogenesis
DOI 10.1007/s10456-024-09934-8PMC PMC11564399

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Abstract

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.

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Metadata

Authors
Kapp, F. G., Bazgir, F., Mahammadzade, N., Mehrabipour, M., Vassella, E., Bernhard, S. M., Döring, Y., Holm, A., Karow, A., Seebauer, C., Platz Batista da Silva, N., Wohlgemuth, W. A., Oppenheimer, A., Kröning, P., Niemeyer, C. M., Schanze, D., Zenker, M., Eng, W., Ahmadian, M. R., Baumgartner, I., & Rössler, J.
Affiliations
  • University of Freiburg (DE)
  • Düsseldorf University Hospital (DE)
  • University of Bern (CH)
  • Boston Children's Hospital (US)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • University Hospital Regensburg (DE)
  • Martin Luther University Halle-Wittenberg (DE)
  • University Hospital Magdeburg (DE)
Corresponding author
  • Kapp, Friedrich G.
  • Rössler, Jochen
ORCID
Venue
Angiogenesis
Publisher
Springer Science and Business Media LLC
Published
2024-07-05
Volume
27
Issue
4
Pages
739-752
ISSN
  • 0969-6970 (ISSN-L)
  • 1573-7209
DOI
10.1007/s10456-024-09934-8
PMC
PMC11564399
OpenAlex
W4400354308
Cited by
20
References
1
Citations by year
2026: 13 · 2025: 7
FWCI
8.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Angiogenesis (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
  • PUBLISSO (German National Library of Medicine) (submittedVersion, cc-by)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
Funders
  • Charity cycling tour “Tour der Hoffnung”
  • Deutsche Forschungsgemeinschaft (DFG AH 92/8-3, IRTG 1902-p6)
  • DFG Walter Benjamin Fellowship (458322953)
  • German Federal Ministry of Education and Research (FKZ 01GM1902A, 01GM1902C)
  • Swiss National Research Foundation, Synergia grant (CRSII5_193694 2021-2024)
  • Universitätsklinikum Freiburg
Topics
  • Health Sciences › Medicine › Surgery › Vascular Malformations and Hemangiomas
  • Health Sciences › Medicine › Clinical Neurology › Vascular Malformations Diagnosis and Treatment
  • Health Sciences › Medicine › Genetics (clinical) › Vascular Anomalies and Treatments
Keywords
arteriovenous malformation, RIT1, somatic deletions, RAS/MAPK pathway, MEK inhibition, trametinib, bleeding events, targeted therapy
MeSH terms
Animals, Arteriovenous Malformations, Female, Humans, Male, Pyridones, Pyrimidinones, Zebrafish, ras Proteins, MAP Kinase Signaling System, Protein Kinase Inhibitors, HEK293 Cells

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