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Here, we identify a venous-specific signaling circuit driving disease progression, where excessive PI3K\u03b1 activity amplifies upstream TIE2 receptor signaling through autocrine and paracrine mechanisms. In <jats:italic>Pik3ca<\/jats:italic>\n            <jats:sup>\n              <jats:italic>H1047R<\/jats:italic>\n            <\/jats: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\u2013FOXO1\u2013ANGPT\u2013TIE2 circuit as a core driver of PIK3CA-related VMs and highlight TIE2 as a promising therapeutic target.<\/jats:p>","DOI":"10.1038\/s44161-025-00655-9","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T06:04:15Z","timestamp":1747980255000},"page":"801-820","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Angiopoietin\u2013TIE2 feedforward circuit promotes PIK3CA-driven venous malformations"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3523-7003","authenticated-orcid":false,"given":"Marle","family":"Kraft","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3429-912X","authenticated-orcid":false,"given":"Hans","family":"Schoofs","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7186-7256","authenticated-orcid":false,"given":"Milena","family":"Petkova","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4577-8620","authenticated-orcid":false,"given":"Jorge","family":"Andrade","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6974-4209","authenticated-orcid":false,"given":"Ana Rita","family":"Grosso","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2458-3055","authenticated-orcid":false,"given":"Rui","family":"Benedito","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0000-1260","authenticated-orcid":false,"given":"An-Katrien","family":"De Roo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8273-3328","authenticated-orcid":false,"given":"Laurence M.","family":"Boon","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6236-338X","authenticated-orcid":false,"given":"Miikka","family":"Vikkula","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2729-6177","authenticated-orcid":false,"given":"Friedrich G.","family":"Kapp","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6830-2043","authenticated-orcid":false,"given":"Ren\u00e9","family":"H\u00e4gerling","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5689-0036","authenticated-orcid":false,"given":"Michael","family":"Potente","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9338-1257","authenticated-orcid":false,"given":"Taija","family":"M\u00e4kinen","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"655_CR1","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1161\/CIRCRESAHA.121.318145","volume":"129","author":"A Queisser","year":"2021","unstructured":"Queisser, A., Seront, E., Boon, L. 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