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Kraft M, Schoofs H, Petkova M, Andrade J, Grosso AR, Benedito R, De Roo AK, Boon LM, Vikkula M, Kapp FG, Hägerling R, Potente M, Mäkinen T
Nat Cardiovasc Res 4 (7) 801-820 [2025-07-00; online 2025-05-23]
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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PubMed 40410415
DOI 10.1038/s44161-025-00655-9
Crossref 10.1038/s44161-025-00655-9
pmc: PMC12259471
pii: 10.1038/s44161-025-00655-9