Related Experiment Video
Updated: Sep 20, 2025
06:51
A Patient-Derived Xenograft Model for Venous Malformation
Published on: June 15, 2020
5.5K
Angiopoietin-TIE2 feedforward circuit promotes PIK3CA-driven venous malformations
Marle Kraft1, Hans Schoofs1, Milena Petkova1
1Uppsala University, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
Nature Cardiovascular Research
|May 23, 2025
Summary
Somatic PIK3CA mutations cause venous malformations (VMs). This study identifies a PI3K-FOXO1-ANGPT-TIE2 signaling circuit driving VM progression, revealing TIE2 as a potential therapeutic target for these vascular anomalies.
Area of Science:
- Vascular biology
- Molecular genetics
- Cancer signaling pathways
Background:
- Venous malformations (VMs) are common vascular anomalies lacking effective treatments.
- Somatic PIK3CA mutations frequently drive VM pathogenesis by activating the PI3Kα-AKT-mTOR pathway.
Purpose of the Study:
- To elucidate the specific signaling mechanisms underlying PIK3CA-mutant VM progression.
- To identify novel therapeutic targets for VMs.
Main Methods:
- Utilized PIK3CAH1047R-driven VM mouse models.
- Performed single-cell transcriptomics and lineage tracking.
- Investigated signaling pathways including PI3K-AKT-mTOR, FOXO1, and ANGPT-TIE2.
Main Results:
- Identified a venous-specific circuit where PI3Kα hyperactivation amplifies TIE2 signaling.
- Observed clonal expansion of mutant endothelial cells with suppressed FOXO1 and ANGPT2.
- Demonstrated that TIE2 or ANGPT inhibition, but not mTOR blockade, suppressed VM growth in mice.
- Found evidence of increased TIE2 activity in both mouse and human VMs.
Conclusions:
- Uncovered a PI3K-FOXO1-ANGPT-TIE2 signaling axis as a critical driver of PIK3CA-related VMs.
- Highlighted TIE2 as a promising therapeutic target for treating venous malformations.
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