Angiopoietin–TIE2 feedforward circuit promotes PIK3CA-driven venous malformations
(2025) Nature Cardiovascular Research — (2025)
Files
s44161-025-00655-9.pdf
Open Access - Adobe PDF
- 27.66 MB
Details
- Authors
Kraft, Marle 
Schoofs, Hans Petkova, Milena Andrade, Jorge Mäkinen, Taija
- Abstract
- Venous malformations (VMs) are vascular anomalies lacking curative treatments, often caused by somatic PIK3CA mutations that hyperactivate the PI3Kα–AKT–mTOR signaling pathway. Here, we identify a venous-specific signaling circuit driving disease progression, where excessive PI3Kα activity amplifies upstream TIE2 receptor signaling through autocrine and paracrine mechanisms. In Pik3caH1047R-driven VM mouse models, single-cell transcriptomics and lineage tracking revealed clonal expansion of mutant endothelial cells with a post-capillary venous phenotype, characterized by suppression of the AKT-inhibited FOXO1 and its target genes, including the TIE2 antagonist ANGPT2. An imbalance in TIE2 ligands, likely exacerbated by aberrant recruitment of smooth muscle cells producing the agonist ANGPT1, increased TIE2 activity in both mouse and human VMs. While mTOR blockade had limited effects on advanced VMs in mice, inhibiting TIE2 or ANGPT effectively suppressed their growth. These findings uncover a PI3K–FOXO1–ANGPT–TIE2 circuit as a core driver of PIK3CA-related VMs and highlight TIE2 as a promising therapeutic target.
- Affiliations
Uppsala University Department of Immunology, Genetics and Pathology Berlin Institute of Health at Charité – Universitätsmedizin Berlin Angiogenesis & Metabolism Laboratory,Department of Immunology, Genetics and Pathology Max Delbrück Center for Molecular Medicine in the Helmholtz Association NOVA School of Science and Technology,Universidade NOVA de Lisboa Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology,Universidade NOVA de Lisboa UCIBIO – Applied Molecular Biosciences Unit, Department of Life Sciences Centro Nacional de Investigaciones Cardiovasculares (CNIC) Molecular Genetics of Angiogenesis Group WELBIO research institute WELBIO department Children’s Hospital, Medical Center - University of Freiburg, Department of Pediatric Hematology and Oncology, Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin Lymphovascular Medicine and Translational 3D-Histopathology’ Berlin Institute of Health at Charité-Universitätsmedizin Berlin BIH Center for Regenerative Therapies, University of Helsinki, Translational Cancer Medicine Program and Department of Biochemistry and Developmental Biology Wihuri Research Institute, Helsinki,
Citations
Kraft, M., Schoofs, H., Petkova, M., Andrade, J., Grosso, A. R., Benedito, R., De Roo, A.-K., Boon, L., Vikkula, M., Kapp, F. G., Hägerling, R., Potente, M., & Mäkinen, T. (2025). Angiopoietin–TIE2 feedforward circuit promotes PIK3CA-driven venous malformations. Nature Cardiovascular Research. Published. https://doi.org/10.1038/s44161-025-00655-9 (Original work published 2025)