Angiopoietin–TIE2 feedforward circuit promotes PIK3CA-driven venous malformations

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.

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Funding Information: The computations of scRNA-seq data were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) partially funded by the Swedish Research Council through grant agreement no. 2018-05973, and the National Academic Infrastructure for Supercomputing in Sweden (NAISS), partially funded by the Swedish Research Council through grant agreement no. 2022-06725, under projects NAISS 2023/22-192 and NAISS 2023/23-457. This work was supported by grants from the Knut and Alice Wallenberg Foundation (2018.0218 and 2020.0057; to T.M.), the Swedish Research Council (2020-0269; to T.M.), Göran Gustafsson foundation (to T.M.), the Swedish Cancer Society (19 0220 Pj, 22 2025 Pj; to T.M.), Sigrid Juselius Foundation (240137; to T.M.), the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement (no. 814316; to M.K., H.S., M. Po, T.M. and M.V.), Fonds de la Recherche Scientifique - FNRS grants T.0240.23 and P.C005.22 (to M.V.), T.00.19.22 and P.C013.20 (to L.M.B.), Fondation Saint Luc (to L.M.B.), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO IP X.1548.24; to M.V.), the European Research Council Consolidator Grant EMERGE (no. 773047; to M. Po), the Deutsche Forschungsgemeinschaft (DFG, project number 456687919 – SFB 1531; to M. Po), the Leducq Foundation (to M. Po and M.V.), European Research Council Starting Grant PREVENT (no. 101078827; to R.H.), the charity cycling tour ‘Tour der Hoffnung’ (to F.K.), EJPRD Joint Transnational Call 2023, NARRATIVE (to L.M.B.); FKZ 01GM2405 (to F.K.). A.-K.D.R., L.M.B., M.V. and F.K. are members of the VASCA Working Group of the European Reference Network for Rare Multisystemic Vascular Diseases (project identification no. 769036). Open access funding provided by Uppsala University. Publisher Copyright: © The Author(s) 2025.

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Biochemistry, Genetics and Molecular Biology (miscellaneous) Cell Biology Medicine (miscellaneous) Cardiology and Cardiovascular Medicine SDG 3 - Good Health and Well-being