{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:03:57Z","timestamp":1787313837766,"version":"build-2736575974"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T00:00:00Z","timestamp":1777766400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T00:00:00Z","timestamp":1777766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100006196","name":"University of Oulu","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Angiogenesis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Venous malformations (VMs) are developmental defects in vascular morphogenesis characterized by enlarged vein-like channels and defective perivascular cell coverage. The majority of VMs are caused by somatic mutations in endothelial cell (EC) receptor tyrosine kinase TIE2, but current medicinal options are limited. The common bottleneck when testing new therapeutic strategies and identifying efficient drug candidates is the absence of a reliable and robust model for replicating the characteristics of VMs. We report here on an advanced in vitro model for recapitulating cellular and molecular pathologies of the VM-causative\n                    <jats:italic>TIE2<\/jats:italic>\n                    <jats:sup>L914F<\/jats:sup>\n                    mutation by co-culturing human adipose tissue-derived stem cells (hASCs) with either human umbilical vein ECs (HUVECs) retrovirally transduced to express\n                    <jats:italic>TIE2<\/jats:italic>\n                    <jats:sup>L914F<\/jats:sup>\n                    or with induced pluripotent stem cell-derived ECs (iECs) with locus-targeted\n                    <jats:italic>TIE2<\/jats:italic>\n                    <jats:sup>L914F<\/jats:sup>\n                    . For comparison, cellular and molecular crosstalk between vascular cell types was investigated in HUVEC and primary vascular smooth muscle cell (vSMC) co-cultures. Advanced microscopy and transcriptomic analysis were used to investigate the cellular and molecular phenotypes in vascular cell types. Comparison of\n                    <jats:italic>TIE2<\/jats:italic>\n                    <jats:sup>WT<\/jats:sup>\n                    , gain- (\n                    <jats:italic>TIE2<\/jats:italic>\n                    <jats:sup>L914F<\/jats:sup>\n                    ) and loss-of-function mutations (\n                    <jats:italic>TIE2<\/jats:italic>\n                    <jats:sup>KO<\/jats:sup>\n                    ) revealed the importance of TIE2 signaling for vascular network formation in hASC\/EC co-cultures. The model recapitulated the cellular hallmarks of the VMs and revealed gene signatures and signaling pathways relevant to VM pathologies. The data also demonstrated the utility of the hASC\/EC model as a screening platform for VM pharmacotherapies. Overall, this work establishes a versatile platform for studying disease mechanisms affecting the vasculature and provides new insights into VM pathobiology and screening potential for therapeutic applications targeting VMs.\n                  <\/jats:p>","DOI":"10.1007\/s10456-026-10045-9","type":"journal-article","created":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T20:59:35Z","timestamp":1777841975000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A human endothelial and adipose stem cell-based co-culture model for venous malformations"],"prefix":"10.1007","volume":"29","author":[{"given":"Mohammadhassan","family":"Ansarizadeh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojana","family":"Lazovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Sarmadian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Hicks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauri","family":"Eklund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,3]]},"reference":[{"key":"10045_CR1","doi-asserted-by":"publisher","first-page":"13950","DOI":"10.1038\/s41598-023-41278-z","volume":"13","author":"JY Ryu","year":"2023","unstructured":"Ryu JY, Chang YJ, Lee JS et al (2023) A nationwide cohort study on incidence and mortality associated with extracranial vascular malformations. Sci Rep 13:13950. https:\/\/doi.org\/10.1038\/s41598-023-41278-z","journal-title":"Sci Rep"},{"key":"10045_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sempedsurg.2020.150967","volume":"29","author":"HL Nguyen","year":"2020","unstructured":"Nguyen HL, Boon LM, Vikkula M (2020) Genetics of vascular anomalies. Semin Pediatr Surg 29:150967. https:\/\/doi.org\/10.1016\/j.sempedsurg.2020.150967","journal-title":"Semin Pediatr Surg"},{"key":"10045_CR3","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.avsg.2011.12.004","volume":"26","author":"YN Roh","year":"2012","unstructured":"Roh YN, Do YS, Park KB et al (2012) The results of surgical treatment for patients with venous malformations. Ann Vasc Surg 26:665\u2013673. https:\/\/doi.org\/10.1016\/j.avsg.2011.12.004","journal-title":"Ann Vasc Surg"},{"key":"10045_CR4","doi-asserted-by":"publisher","first-page":"557","DOI":"10.21037\/cdt.2016.11.10","volume":"6","author":"S Behravesh","year":"2016","unstructured":"Behravesh S, Yakes W, Gupta N et al (2016) Venous malformations: clinical diagnosis and treatment. Cardiovasc Diagn Ther 6:557\u2013569 https:\/\/doi.org\/10.21037\/cdt.2016.11.10","journal-title":"Cardiovasc Diagn Ther"},{"key":"10045_CR5","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1016\/S0092-8674(00)81814-0","volume":"87","author":"M Vikkula","year":"1996","unstructured":"Vikkula M, Boon LM, Iii KLC et al (1996) Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87:1181\u20131190. https:\/\/doi.org\/10.1016\/S0092-8674(00)81814-0","journal-title":"Cell"},{"key":"10045_CR6","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1186\/s12964-020-00606-w","volume":"18","author":"Y Si","year":"2020","unstructured":"Si Y, Huang J, Li X et al (2020) AKT\/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations. Cell Commun Signal 18:139. https:\/\/doi.org\/10.1186\/s12964-020-00606-w","journal-title":"Cell Commun Signal"},{"key":"10045_CR7","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.humpath.2024.02.004","volume":"145","author":"K Hirose","year":"2024","unstructured":"Hirose K, Hori Y, Ozeki M et al (2024) Comprehensive phenotypic and genomic characterization of venous malformations. Hum Pathol 145:48\u201355. https:\/\/doi.org\/10.1016\/j.humpath.2024.02.004","journal-title":"Hum Pathol"},{"key":"10045_CR8","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1203\/01.PDR.0000155761.70710.C4","volume":"57","author":"S Diehl","year":"2005","unstructured":"Diehl S, Bruno R, Wilkinson GA et al (2005) Altered expression patterns of ephrinB2 and EphB2 in human umbilical vessels and congenital venous malformations. Pediatr Res 57:537\u2013544. https:\/\/doi.org\/10.1203\/01.PDR.0000155761.70710.C4","journal-title":"Pediatr Res"},{"key":"10045_CR9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0252342","volume":"16","author":"MJ Schonning","year":"2021","unstructured":"Schonning MJ, Koh S, Sun RW et al (2021) Venous malformation vessels are improperly specified and hyperproliferative. PLoS ONE 16:e0252342. https:\/\/doi.org\/10.1371\/journal.pone.0252342","journal-title":"PLoS ONE"},{"key":"10045_CR10","doi-asserted-by":"publisher","first-page":"6374","DOI":"10.1093\/hmg\/ddv349","volume":"24","author":"M N\u00e4tynki","year":"2015","unstructured":"N\u00e4tynki M, Kangas J, Miinalainen I et al (2015) Common and specific effects of TIE2 mutations causing venous malformations. Hum Mol Genet 24:6374\u20136389. https:\/\/doi.org\/10.1093\/hmg\/ddv349","journal-title":"Hum Mol Genet"},{"key":"10045_CR11","doi-asserted-by":"publisher","first-page":"5457","DOI":"10.1038\/srep05457","volume":"4","author":"G Chen","year":"2014","unstructured":"Chen G, Ren JG, Zhang W et al (2014) Disorganized vascular structures in sporadic venous malformations: a possible correlation with balancing effect between Tie2 and TGF-2. Sci Rep 4:5457. https:\/\/doi.org\/10.1038\/srep05457","journal-title":"Sci Rep"},{"key":"10045_CR12","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1007\/s00441-022-03657-2","volume":"389","author":"GH Chen","year":"2022","unstructured":"Chen GH, Yang JG, Xia HF et al (2022) Endothelial cells induce degradation of ECM through enhanced secretion of MMP14 carried on extracellular vesicles in venous malformation. Cell Tissue Res 389:517\u2013530. https:\/\/doi.org\/10.1007\/s00441-022-03657-2","journal-title":"Cell Tissue Res"},{"key":"10045_CR13","doi-asserted-by":"publisher","DOI":"10.1038\/ng.272","author":"N Limaye","year":"2009","unstructured":"Limaye N, Wouters V, Uebelhoer M et al (2009) Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet. https:\/\/doi.org\/10.1038\/ng.272","journal-title":"Nat Genet"},{"key":"10045_CR14","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1159\/000348327","volume":"4","author":"J Soblet","year":"2013","unstructured":"Soblet J, Limaye N, Uebelhoer M et al (2013) Variable somatic TIE2 mutations in half of sporadic venous malformations. Mol Syndromol 4:179\u2013183. https:\/\/doi.org\/10.1159\/000348327","journal-title":"Mol Syndromol"},{"key":"10045_CR15","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1097\/01.prs.0000371800.69031.6b","volume":"125","author":"A Hassanein","year":"2010","unstructured":"Hassanein A, Mulliken J, Fishman S, Greene A (2010) 64C: Venous malformation: natural progression and recurrence after treatment. Plast Reconstr Surg 125:517\u2013530. https:\/\/doi.org\/10.1097\/01.prs.0000371800.69031.6b","journal-title":"Plast Reconstr Surg"},{"key":"10045_CR16","doi-asserted-by":"publisher","first-page":"1099328","DOI":"10.3389\/fneur.2023.1099328","volume":"14","author":"A Mansur","year":"2023","unstructured":"Mansur A, Radovanovic I (2023) Vascular malformations: an overview of their molecular pathways, detection of mutational profiles and subsequent targets for drug therapy. Front Neurol 14:1099328. https:\/\/doi.org\/10.3389\/fneur.2023.1099328","journal-title":"Front Neurol"},{"key":"10045_CR17","doi-asserted-by":"publisher","first-page":"312","DOI":"10.3390\/children8040312","volume":"8","author":"J Aronniemi","year":"2021","unstructured":"Aronniemi J, L\u00e5ngstr\u00f6m S, Mattila KA et al (2021) Venous malformations and blood coagulation in children. Children 8:312. https:\/\/doi.org\/10.3390\/children8040312","journal-title":"Children"},{"key":"10045_CR18","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.30215","volume":"70","author":"ER Engel","year":"2023","unstructured":"Engel ER, Hammill A, Adams D et al (2023) Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: impact on symptomatology, quality of life, and radiographic response. Pediatr Blood Cancer 70:e30215. https:\/\/doi.org\/10.1002\/pbc.30215","journal-title":"Pediatr Blood Cancer"},{"key":"10045_CR19","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/bcpt.13027","volume":"123","author":"J Kangas","year":"2018","unstructured":"Kangas J, N\u00e4tynki M, Eklund L (2018) Development of molecular therapies for venous malformations. Basic Clin Pharmacol Toxicol 123:6\u201319. https:\/\/doi.org\/10.1111\/bcpt.13027","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"10045_CR20","doi-asserted-by":"publisher","DOI":"10.14573\/altex.1411271","author":"O Huttala","year":"2015","unstructured":"Huttala O, Vuorenp\u00e4\u00e4 H, Toimela T et al (2015) Human vascular model with defined stimulation medium\u2014a characterization study. Altex. https:\/\/doi.org\/10.14573\/altex.1411271","journal-title":"Altex"},{"key":"10045_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2021.119157","volume":"1869","author":"I Beloglazova","year":"2022","unstructured":"Beloglazova I, Stepanova V, Zubkova E et al (2022) Mesenchymal stromal cells enhance self-assembly of a HUVEC tubular network through uPA-uPAR\/VEGFR2\/integrin\/NOTCH crosstalk. Biochim Biophys Acta Mol Cell Res 1869:119157. https:\/\/doi.org\/10.1016\/j.bbamcr.2021.119157","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"key":"10045_CR22","doi-asserted-by":"publisher","first-page":"15113","DOI":"10.1038\/s41598-024-64263-6","volume":"14","author":"G Nie","year":"2024","unstructured":"Nie G, Zhang H, Luo W et al (2024) Enhancement of endothelial function and attenuation of portal vein injury using mesenchymal stem cells carrying miRNA-25-3p. Sci Rep 14:15113. https:\/\/doi.org\/10.1038\/s41598-024-64263-6","journal-title":"Sci Rep"},{"key":"10045_CR23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0278895","volume":"17","author":"S Summer","year":"2022","unstructured":"Summer S, Rossmanith E, Pasztorek M et al (2022) Mesenchymal stem cells support human vascular endothelial cells to form vascular sprouts in human platelet lysate-based matrices. PLoS ONE 17:e0278895. https:\/\/doi.org\/10.1371\/journal.pone.0278895","journal-title":"PLoS ONE"},{"key":"10045_CR24","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1039\/D4LC00824C","volume":"25","author":"M Ansarizadeh","year":"2025","unstructured":"Ansarizadeh M, Nguyen H-T, Lazovic B et al (2025) Microfluidic vessel-on-chip platform for investigation of cellular defects in venous malformations and responses to various shear stress and flow conditions. Lab Chip 25:613\u2013630. https:\/\/doi.org\/10.1039\/D4LC00824C","journal-title":"Lab Chip"},{"key":"10045_CR25","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-024-09925-9","author":"B Lazovic","year":"2024","unstructured":"Lazovic B, Nguyen H-T, Ansarizadeh M et al (2024) Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells. Angiogenesis. https:\/\/doi.org\/10.1007\/s10456-024-09925-9","journal-title":"Angiogenesis"},{"key":"10045_CR26","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1161\/01.CIR.0000121425.42966.F1","volume":"109","author":"J Rehman","year":"2004","unstructured":"Rehman J, Traktuev D, Li J et al (2004) Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 109:1292\u20131298. https:\/\/doi.org\/10.1161\/01.CIR.0000121425.42966.F1","journal-title":"Circulation"},{"key":"10045_CR27","doi-asserted-by":"publisher","first-page":"10890","DOI":"10.3390\/ijms221910890","volume":"22","author":"S Rautiainen","year":"2021","unstructured":"Rautiainen S, Laaksonen T, Koivuniemi R (2021) Angiogenic effects and crosstalk of adipose-derived mesenchymal stem\/stromal cells and their extracellular vesicles with endothelial cells. Int J Mol Sci 22:10890. https:\/\/doi.org\/10.3390\/ijms221910890","journal-title":"Int J Mol Sci"},{"key":"10045_CR28","doi-asserted-by":"publisher","first-page":"17048","DOI":"10.1038\/boneres.2017.48","volume":"5","author":"X Cai","year":"2017","unstructured":"Cai X, Xie J, Yao Y et al (2017) Angiogenesis in a 3D model containing adipose tissue stem cells and endothelial cells is mediated by canonical Wnt signaling. Bone Res 5:17048. https:\/\/doi.org\/10.1038\/boneres.2017.48","journal-title":"Bone Res"},{"key":"10045_CR29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.07.034","author":"J Soblet","year":"2017","unstructured":"Soblet J, Kangas J, N\u00e4tynki M et al (2017) Blue rubber bleb nevus (BRBN) syndrome is caused by somatic TEK (TIE2) mutations. J Investig Dermatol. https:\/\/doi.org\/10.1016\/j.jid.2016.07.034","journal-title":"J Investig Dermatol"},{"key":"10045_CR30","doi-asserted-by":"publisher","first-page":"4903","DOI":"10.1038\/s41467-020-18548-9","volume":"11","author":"A Lundin","year":"2020","unstructured":"Lundin A, Porritt MJ, Jaiswal H et al (2020) Development of an ObLiGaRe doxycycline inducible Cas9 system for pre-clinical cancer drug discovery. Nat Commun 11:4903. https:\/\/doi.org\/10.1038\/s41467-020-18548-9","journal-title":"Nat Commun"},{"key":"10045_CR31","doi-asserted-by":"publisher","first-page":"2518","DOI":"10.7150\/ijms.102700","volume":"22","author":"D Zhong","year":"2025","unstructured":"Zhong D, Fan Y, You YH et al (2025) Endothelial TIE2 mutation induced contraction deficiency of vascular smooth muscle cells via phenotypic transition regulation in venous malformations. Int J Med Sci 22:2518\u20132532. https:\/\/doi.org\/10.7150\/ijms.102700","journal-title":"Int J Med Sci"},{"key":"10045_CR32","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1111\/j.1538-7836.2011.04275.x","volume":"9","author":"N Takakura","year":"2011","unstructured":"Takakura N (2011) Role of intimate interactions between endothelial cells and the surrounding accessory cells in the maturation of blood vessels. J Thromb Haemost 9:144\u2013150. https:\/\/doi.org\/10.1111\/j.1538-7836.2011.04275.x","journal-title":"J Thromb Haemost"},{"key":"10045_CR33","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/nrc1094","volume":"3","author":"R Kalluri","year":"2003","unstructured":"Kalluri R (2003) Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 3:422\u2013433. https:\/\/doi.org\/10.1038\/nrc1094","journal-title":"Nat Rev Cancer"},{"key":"10045_CR34","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1001\/jamadermatol.2021.3459","volume":"157","author":"A Maruani","year":"2021","unstructured":"Maruani A, Tavernier E, Boccara O et al (2021) Sirolimus (rapamycin) for slow-flow malformations in children: the observational-phase randomized clinical PERFORMUS trial. JAMA Dermatol 157:144\u2013150. https:\/\/doi.org\/10.1001\/jamadermatol.2021.3459","journal-title":"JAMA Dermatol"},{"key":"10045_CR35","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.857436","volume":"10","author":"A Karastaneva","year":"2022","unstructured":"Karastaneva A, Gasparella P, Tschauner S et al (2022) Indications and limitations of sirolimus in the treatment of vascular anomalies\u2014insights from a retrospective case series. Front Pediatr 10:857436. https:\/\/doi.org\/10.3389\/fped.2022.857436","journal-title":"Front Pediatr"},{"key":"10045_CR36","doi-asserted-by":"publisher","first-page":"3081","DOI":"10.1016\/j.radcr.2025.03.016","volume":"20","author":"DK Carolino","year":"2025","unstructured":"Carolino DK, Muramatsu K, Tani Y et al (2025) The use of sirolimus for an unresectable and refractory venous malformation: a case series. Radiol Case Reports 20:3081\u20133085. https:\/\/doi.org\/10.1016\/j.radcr.2025.03.016","journal-title":"Radiol Case Reports"},{"key":"10045_CR37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvsv.2025.102284","volume":"13","author":"G Wang","year":"2025","unstructured":"Wang G, Lu W, Zhu Y et al (2025) Effectiveness and safety of sirolimus in the treatment of venous malformations: a meta-analysis of prospective studies. J Vasc Surg Venous Lymphat Disord 13:102284. https:\/\/doi.org\/10.1016\/j.jvsv.2025.102284","journal-title":"J Vasc Surg Venous Lymphat Disord"},{"key":"10045_CR38","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1080\/08880018.2025.2498660","volume":"42","author":"A Etingin","year":"2025","unstructured":"Etingin A, Remy A, Sonea T et al (2025) Alpelisib in pediatric PIK3CA- and TIE-2\u2013mutant vascular anomalies: a case series on safety, efficacy, and drug exposure. Pediatr Hematol Oncol 42:228\u2013241. https:\/\/doi.org\/10.1080\/08880018.2025.2498660","journal-title":"Pediatr Hematol Oncol"},{"key":"10045_CR39","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.732836","volume":"9","author":"A Pagliazzi","year":"2021","unstructured":"Pagliazzi A, Oranges T, Traficante G et al (2021) PIK3CA-related overgrowth spectrum from diagnosis to targeted therapy: a case of CLOVES syndrome treated with alpelisib. Front Pediatr 9:732836. https:\/\/doi.org\/10.3389\/fped.2021.732836","journal-title":"Front Pediatr"},{"key":"10045_CR40","doi-asserted-by":"publisher","first-page":"10499","DOI":"10.1038\/s41598-023-37468-4","volume":"13","author":"M Sterba","year":"2023","unstructured":"Sterba M, Pokorna P, Faberova R et al (2023) Targeted treatment of severe vascular malformations harboring PIK3CA and TEK mutations with alpelisib is highly effective with limited toxicity. Sci Rep 13:10499. https:\/\/doi.org\/10.1038\/s41598-023-37468-4","journal-title":"Sci Rep"},{"key":"10045_CR41","doi-asserted-by":"publisher","DOI":"10.1016\/j.oooo.2025.05.009","author":"Y-SL Cheng","year":"2025","unstructured":"Cheng Y-SL, Bustamante D, Yates DM et al (2025) TEK-related venous malformation of the orofacial region: report of a case with multidisciplinary treatment guided by molecular diagnosis. Oral Surg Oral Med Oral Pathol Oral Radiol. https:\/\/doi.org\/10.1016\/j.oooo.2025.05.009","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol"},{"key":"10045_CR42","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.29897","volume":"69","author":"A Remy","year":"2022","unstructured":"Remy A, Tran TH, Dubois J et al (2022) Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: preliminary pharmacokinetics and pharmacodynamic data. Pediatr Blood Cancer 69:e29897. https:\/\/doi.org\/10.1002\/pbc.29897","journal-title":"Pediatr Blood Cancer"},{"key":"10045_CR43","doi-asserted-by":"publisher","first-page":"3491","DOI":"10.1172\/JCI76004","volume":"125","author":"E Boscolo","year":"2015","unstructured":"Boscolo E, Limaye N, Huang L et al (2015) Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J Clin Investig 125:3491\u20133504. https:\/\/doi.org\/10.1172\/JCI76004","journal-title":"J Clin Investig"},{"key":"10045_CR44","doi-asserted-by":"publisher","first-page":"332ra42","DOI":"10.1126\/scitranslmed.aaf1164","volume":"8","author":"P Castel","year":"2016","unstructured":"Castel P, Carmona FJ, Grego-Bessa J et al (2016) Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci Transl Med 8:332ra42. https:\/\/doi.org\/10.1126\/scitranslmed.aaf1164","journal-title":"Sci Transl Med"},{"key":"10045_CR45","doi-asserted-by":"publisher","first-page":"332ra43","DOI":"10.1126\/scitranslmed.aad9982","volume":"8","author":"SD Castillo","year":"2016","unstructured":"Castillo SD, Tzouanacou E, Zaw-Thin M et al (2016) Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans. Sci Transl Med 8:332ra43. https:\/\/doi.org\/10.1126\/scitranslmed.aad9982","journal-title":"Sci Transl Med"},{"key":"10045_CR46","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.70087","author":"LJ Bischoff","year":"2025","unstructured":"Bischoff LJ, Schrenk S, Soroko K et al (2025) Expression of mutant TIE2 p. L914F during mouse development causes embryonic lethality and defects in vascular remodeling. Dev Dyn. https:\/\/doi.org\/10.1002\/dvdy.70087","journal-title":"Dev Dyn"},{"key":"10045_CR47","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1258\/phleb.2009.009041","volume":"25","author":"A Dompmartin","year":"2010","unstructured":"Dompmartin A, Vikkula M, Boon LM (2010) Venous malformation: update on aetiopathogenesis, diagnosis and management. Phlebol J Venous Dis 25:224\u2013235. https:\/\/doi.org\/10.1258\/phleb.2009.009041","journal-title":"Phlebol J Venous Dis"},{"key":"10045_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-025-00655-9","author":"M Kraft","year":"2025","unstructured":"Kraft M, Schoofs H, Petkova M et al (2025) Angiopoietin\u2013TIE2 feedforward circuit promotes PIK3CA-driven venous malformations. Nat Cardiovasc Res. https:\/\/doi.org\/10.1038\/s44161-025-00655-9","journal-title":"Nat Cardiovasc Res"},{"key":"10045_CR49","doi-asserted-by":"publisher","first-page":"1210563","DOI":"10.3389\/fphys.2023.1210563","volume":"14","author":"S Nakisli","year":"2023","unstructured":"Nakisli S, Lagares A, Nielsen CM, Cuervo H (2023) Pericytes and vascular smooth muscle cells in central nervous system arteriovenous malformations. Front Physiol 14:1210563. https:\/\/doi.org\/10.3389\/fphys.2023.1210563","journal-title":"Front Physiol"},{"key":"10045_CR50","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1186\/s12964-022-00993-2","volume":"20","author":"G Cao","year":"2022","unstructured":"Cao G, Xuan X, Hu J et al (2022) How vascular smooth muscle cell phenotype switching contributes to vascular disease. Cell Commun Signal 20:180. https:\/\/doi.org\/10.1186\/s12964-022-00993-2","journal-title":"Cell Commun Signal"},{"key":"10045_CR51","doi-asserted-by":"publisher","first-page":"3438","DOI":"10.1093\/hmg\/ddt198","volume":"22","author":"M Uebelhoer","year":"2013","unstructured":"Uebelhoer M, N\u00e4tynki M, Kangas J et al (2013) Venous malformation-causative TIE2 mutations mediate an AKT-dependent decrease in PDGFB. Hum Mol Genet 22:3438\u20133448. https:\/\/doi.org\/10.1093\/hmg\/ddt198","journal-title":"Hum Mol Genet"},{"key":"10045_CR52","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","volume":"10","author":"Y Zhou","year":"2019","unstructured":"Zhou Y, Zhou B, Pache L et al (2019) Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10:1523. https:\/\/doi.org\/10.1038\/s41467-019-09234-6","journal-title":"Nat Commun"},{"key":"10045_CR53","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/376070a0","volume":"376","author":"TN Sato","year":"1995","unstructured":"Sato TN, Tozawa Y, Deutsch U et al (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376:70\u201374. https:\/\/doi.org\/10.1038\/376070a0","journal-title":"Nature"},{"key":"10045_CR54","doi-asserted-by":"publisher","first-page":"4320","DOI":"10.1172\/JCI77162","volume":"124","author":"BR Thomson","year":"2014","unstructured":"Thomson BR, Heinen S, Jeansson M et al (2014) A lymphatic defect causes ocular hypertension and glaucoma in mice. J Clin Investig 124:4320\u20134324. https:\/\/doi.org\/10.1172\/JCI77162","journal-title":"J Clin Investig"},{"key":"10045_CR55","doi-asserted-by":"publisher","first-page":"1761","DOI":"10.1016\/j.celrep.2015.08.024","volume":"12","author":"S Savant","year":"2015","unstructured":"Savant S, La Porta S, Budnik A et al (2015) The orphan receptor Tie1 controls angiogenesis and vascular remodeling by differentially regulating tie2 in tip and stalk cells. Cell Rep 12:1761\u20131773. https:\/\/doi.org\/10.1016\/j.celrep.2015.08.024","journal-title":"Cell Rep"},{"key":"10045_CR56","doi-asserted-by":"publisher","first-page":"4025","DOI":"10.1182\/blood-2010-02-270819","volume":"116","author":"R Del Toro","year":"2010","unstructured":"Del Toro R, Prahst C, Mathivet T et al (2010) Identification and functional analysis of endothelial tip cell-enriched genes. Blood 116:4025\u20134033. https:\/\/doi.org\/10.1182\/blood-2010-02-270819","journal-title":"Blood"},{"key":"10045_CR57","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002125","volume":"13","author":"CA Franco","year":"2015","unstructured":"Franco CA, Jones ML, Bernabeu MO et al (2015) Dynamic endothelial cell rearrangements drive developmental vessel regression. PLoS Biol 13:e1002125. https:\/\/doi.org\/10.1371\/journal.pbio.1002125","journal-title":"PLoS Biol"},{"key":"10045_CR58","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1016\/j.yexcr.2013.03.028","volume":"319","author":"CO Lizama","year":"2013","unstructured":"Lizama CO, Zovein AC (2013) Polarizing pathways: balancing endothelial polarity, permeability, and lumen formation. Exp Cell Res 319:1247\u20131254. https:\/\/doi.org\/10.1016\/j.yexcr.2013.03.028","journal-title":"Exp Cell Res"},{"key":"10045_CR59","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/ncb1715","volume":"10","author":"P Saharinen","year":"2008","unstructured":"Saharinen P, Eklund L, Miettinen J et al (2008) Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell\u2013cell and cell\u2013matrix contacts. Nat Cell Biol 10:527\u2013537. https:\/\/doi.org\/10.1038\/ncb1715","journal-title":"Nat Cell Biol"},{"key":"10045_CR60","doi-asserted-by":"publisher","first-page":"12352","DOI":"10.1038\/s41598-019-48854-2","volume":"9","author":"Y Cai","year":"2019","unstructured":"Cai Y, Schrenk S, Goines J et al (2019) Constitutive active mutant TIE2 induces enlarged vascular lumen formation with loss of apico-basal polarity and pericyte recruitment. Sci Rep 9:12352. https:\/\/doi.org\/10.1038\/s41598-019-48854-2","journal-title":"Sci Rep"},{"key":"10045_CR61","doi-asserted-by":"publisher","first-page":"10175","DOI":"10.3390\/ijms221810175","volume":"22","author":"JC Ribeiro-Silva","year":"2021","unstructured":"Ribeiro-Silva JC, Nolasco P, Krieger JE, Miyakawa AA (2021) Dynamic crosstalk between vascular smooth muscle cells and the aged extracellular matrix. Int J Mol Sci 22:10175. https:\/\/doi.org\/10.3390\/ijms221810175","journal-title":"Int J Mol Sci"},{"key":"10045_CR62","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1161\/ATVBAHA.123.318237","volume":"43","author":"PK Lin","year":"2023","unstructured":"Lin PK, Davis GE (2023) Extracellular matrix remodeling in vascular disease: defining its regulators and pathological influence. Arterioscler Thromb Vasc Biol 43:1599\u20131616. https:\/\/doi.org\/10.1161\/ATVBAHA.123.318237","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10045_CR63","doi-asserted-by":"publisher","first-page":"3438","DOI":"10.1093\/hmg\/ddt198","volume":"22","author":"M Uebelhoer","year":"2013","unstructured":"Uebelhoer M, N\u00e4tynki M et al (2013) Venous malformation-causative TIE2 mutations mediate an AKT-dependent decrease in PDGFB. Hum Mol Genet 22:3438\u20133448 https:\/\/doi.org\/10.1093\/hmg\/ddt198","journal-title":"Hum Mol Genet"},{"key":"10045_CR64","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1089\/107632701300062859","volume":"7","author":"PA Zuk","year":"2001","unstructured":"Zuk PA, Zhu M, Mizuno H et al (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7:211\u2013228. https:\/\/doi.org\/10.1089\/107632701300062859","journal-title":"Tissue Eng"},{"key":"10045_CR65","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1161\/CIRCRESAHA.107.159475","volume":"102","author":"DO Traktuev","year":"2008","unstructured":"Traktuev DO, Merfeld-Clauss S, Li J et al (2008) A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res 102:77\u201385. https:\/\/doi.org\/10.1161\/CIRCRESAHA.107.159475","journal-title":"Circ Res"},{"key":"10045_CR66","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.stem.2008.07.003","volume":"3","author":"M Crisan","year":"2008","unstructured":"Crisan M, Yap S, Casteilla L et al (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301\u2013313. https:\/\/doi.org\/10.1016\/j.stem.2008.07.003","journal-title":"Cell Stem Cell"},{"key":"10045_CR67","doi-asserted-by":"publisher","first-page":"2687","DOI":"10.1016\/j.devcel.2024.06.015","volume":"59","author":"Y Wang","year":"2024","unstructured":"Wang Y, Thottappillil N, Gomez-Salazar M et al (2024) Integrated transcriptomics of human blood vessels defines a spatially controlled niche for early mesenchymal progenitor cells. Dev Cell 59:2687-2703.e6. https:\/\/doi.org\/10.1016\/j.devcel.2024.06.015","journal-title":"Dev Cell"},{"key":"10045_CR68","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2021\/5595172","volume":"2021","author":"E Wolmarans","year":"2021","unstructured":"Wolmarans E, Mellet J, Durandt C et al (2021) Single-cell transcriptome analysis of human adipose-derived stromal cells identifies a contractile cell subpopulation. Stem Cells Int 2021:1\u201312. https:\/\/doi.org\/10.1155\/2021\/5595172","journal-title":"Stem Cells Int"},{"key":"10045_CR69","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1002\/stem.2599","volume":"35","author":"WR Hardy","year":"2017","unstructured":"Hardy WR, Moldovan NI, Moldovan L et al (2017) Transcriptional networks in single perivascular cells sorted from human adipose tissue reveal a hierarchy of mesenchymal stem cells. Stem Cells 35:1273\u20131289. https:\/\/doi.org\/10.1002\/stem.2599","journal-title":"Stem Cells"},{"key":"10045_CR70","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1038\/mt.2013.301","volume":"22","author":"SH Bhang","year":"2014","unstructured":"Bhang SH, Lee S, Shin J-Y et al (2014) Efficacious and clinically relevant conditioned medium of human adipose-derived stem cells for therapeutic angiogenesis. Mol Ther 22:862\u2013872. https:\/\/doi.org\/10.1038\/mt.2013.301","journal-title":"Mol Ther"},{"key":"10045_CR71","doi-asserted-by":"publisher","first-page":"663","DOI":"10.3727\/096368912X655109","volume":"22","author":"L-C Hsiao","year":"2013","unstructured":"Hsiao L-C, Carr C, Chang K-C et al (2013) Stem cell-based therapy for ischemic heart disease. Cell Transplant 22:663\u2013675. https:\/\/doi.org\/10.3727\/096368912X655109","journal-title":"Cell Transplant"},{"key":"10045_CR72","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.11.011","author":"N Limaye","year":"2015","unstructured":"Limaye N, Kangas J, Mendola A et al (2015) Somatic activating PIK3CA mutations cause venous malformation. Am J Hum Genet. https:\/\/doi.org\/10.1016\/j.ajhg.2015.11.011","journal-title":"Am J Hum Genet"},{"key":"10045_CR73","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1161\/ATVBAHA.118.312315","volume":"39","author":"X Li","year":"2019","unstructured":"Li X, Cai Y, Goines J et al (2019) Ponatinib combined with rapamycin causes regression of murine venous malformation. Arterioscler Thromb Vasc Biol 39:496\u2013512. https:\/\/doi.org\/10.1161\/ATVBAHA.118.312315","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10045_CR74","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1089\/ten.tec.2012.0430","volume":"19","author":"ML Moya","year":"2013","unstructured":"Moya ML, Hsu YH, Lee AP et al (2013) In vitro perfused human capillary networks. Tissue Eng Part C Methods 19:730\u2013737. https:\/\/doi.org\/10.1089\/ten.tec.2012.0430","journal-title":"Tissue Eng Part C Methods"},{"key":"10045_CR75","doi-asserted-by":"publisher","first-page":"4189","DOI":"10.1039\/c6lc00910g","volume":"16","author":"S Kim","year":"2016","unstructured":"Kim S, Chung M, Ahn J et al (2016) Interstitial flow regulates the angiogenic response and phenotype of endothelial cells in a 3D culture model. Lab Chip 16:4189\u20134199. https:\/\/doi.org\/10.1039\/c6lc00910g","journal-title":"Lab Chip"},{"key":"10045_CR76","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1159\/000336679","volume":"196","author":"J-R Sarkanen","year":"2012","unstructured":"Sarkanen J-R, Vuorenp\u00e4\u00e4 H, Huttala O et al (2012) Adipose stromal cell tubule network model provides a versatile tool for vascular research and tissue engineering. Cells Tissues Organs 196:385\u2013397. https:\/\/doi.org\/10.1159\/000336679","journal-title":"Cells Tissues Organs"},{"key":"10045_CR77","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1093\/bioinformatics\/btv686","volume":"32","author":"F Piccinini","year":"2016","unstructured":"Piccinini F, Kiss A, Horvath P (2016) Cell tracker (not only) for dummies. Bioinformatics 32:955\u2013957. https:\/\/doi.org\/10.1093\/bioinformatics\/btv686","journal-title":"Bioinformatics"},{"key":"10045_CR78","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550. https:\/\/doi.org\/10.1186\/s13059-014-0550-8","journal-title":"Genome Biol"},{"key":"10045_CR79","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","volume":"16","author":"G Yu","year":"2012","unstructured":"Yu G, Wang LG, Han Y, He QY (2012) ClusterProfiler: an R package for comparing biological themes among gene clusters. Omi A J Integr Biol 16:284\u2013287. https:\/\/doi.org\/10.1089\/omi.2011.0118","journal-title":"Omi A J Integr Biol"}],"container-title":["Angiogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10456-026-10045-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10456-026-10045-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10456-026-10045-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:58:58Z","timestamp":1781650738000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10456-026-10045-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,3]]},"references-count":79,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["10045"],"URL":"https:\/\/doi.org\/10.1007\/s10456-026-10045-9","relation":{},"ISSN":["1573-7209"],"issn-type":[{"value":"1573-7209","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,3]]},"assertion":[{"value":"15 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ryan Hicks was AstraZeneca employee and shareholder. Bojana Lazovic is AstraZeneca employee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The use of human adipose stromal cells (hASCs) obtained from surgical operations was approved by the Ethics Committee of the Pirkanmaa Hospital District, Tampere, Finland (R15161). All donors provided written informed consent in accordance with the Declaration of Helsinki.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical aspects"}}],"article-number":"30"}}