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 Pik3ca<sup>H1047R</sup>-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.
Authors
- Friedrich Kapp (ORCID: https://orcid.org/0000-0002-2729-6177)
- Ana Rita Grosso (ORCID: https://orcid.org/0000-0001-6974-4209)
- Hans Schoofs (ORCID: https://orcid.org/0000-0003-3429-912X)
- An‐Katrien De Roo (ORCID: https://orcid.org/0000-0002-0000-1260)
- Jorge Andrade (ORCID: https://orcid.org/0000-0002-4577-8620)
- René Hägerling (ORCID: https://orcid.org/0000-0002-6830-2043)
- Milena Petkova (ORCID: https://orcid.org/0000-0002-7186-7256)
- Michael Potente (ORCID: https://orcid.org/0000-0002-5689-0036)
- Rui Benedito (ORCID: https://orcid.org/0000-0003-2458-3055)
- Taija Mäkinen (ORCID: https://orcid.org/0000-0002-9338-1257)
- Laurence Myriam Boon (ORCID: https://orcid.org/0000-0001-8273-3328)
- Marle Kraft (ORCID: https://orcid.org/0000-0002-3523-7003)
- Miikka Vikkula (ORCID: https://orcid.org/0000-0002-6236-338X)
Institutions
- Uppsala University (SE)
- Cliniques Universitaires Saint-Luc (BE)
- University of Helsinki (FI)
- Max Delbrück Center (DE)
- University Medical Center Freiburg (DE)
- Spanish National Centre for Cardiovascular Research (ES)
- Wihuri Research Institute (FI)
- de Duve Institute (BE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- Charité - Universitätsmedizin Berlin (DE)
- Universidade Nova de Lisboa (PT)
- UCLouvain (BE)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1038/s44161-025-00655-9
- Citations
- 11
- Primary Topic
- Vascular Malformations and Hemangiomas
- Type
- article
- Field-Weighted Citation Impact
- 22.07