{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:30:47Z","timestamp":1793644247259,"version":"4.5.1"},"reference-count":82,"publisher":"Rockefeller University Press","issue":"4","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2018-05973"],"award-info":[{"award-number":["2018-05973"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2020-0269"],"award-info":[{"award-number":["2020-0269"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004063","name":"Knut and Alice Wallenberg Foundation","doi-asserted-by":"publisher","award":["2018.0218"],"award-info":[{"award-number":["2018.0218"]}],"id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004063","name":"Knut and Alice Wallenberg Foundation","doi-asserted-by":"publisher","award":["2020.0057"],"award-info":[{"award-number":["2020.0057"]}],"id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016408","name":"G\u00f6ran Gustafsson Stiftelser","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016408","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Swedish Cancer Society","doi-asserted-by":"publisher","award":["19 0220 Pj"],"award-info":[{"award-number":["19 0220 Pj"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Swedish Cancer Society","doi-asserted-by":"publisher","award":["19 0219 Us"],"award-info":[{"award-number":["19 0219 Us"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["ERC-2014-CoG-646849"],"award-info":[{"award-number":["ERC-2014-CoG-646849"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["814316"],"award-info":[{"award-number":["814316"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["749731"],"award-info":[{"award-number":["749731"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010434","name":"La Caixa Foundation","doi-asserted-by":"publisher","award":["HR18-00120"],"award-info":[{"award-number":["HR18-00120"]}],"id":[{"id":"10.13039\/100010434","id-type":"DOI","asserted-by":"publisher"}]},{"name":"La Caixa Banking Foundation","award":["LCF\/BQ\/PR20\/11770002"],"award-info":[{"award-number":["LCF\/BQ\/PR20\/11770002"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["STR 1538\/1-1"],"award-info":[{"award-number":["STR 1538\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004410","name":"European Molecular Biology Organization","doi-asserted-by":"publisher","award":["ALTF 86-2017"],"award-info":[{"award-number":["ALTF 86-2017"]}],"id":[{"id":"10.13039\/100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,4,3]]},"abstract":"<jats:p>Oncogenic mutations in PIK3CA, encoding p110\u03b1-PI3K, are a common cause of venous and lymphatic malformations. Vessel type\u2013specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3caH1047R-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3caH1047R mice. Expression of pro-inflammatory genes, including monocyte\/macrophage chemokine Ccl2, in Pik3caH1047R-iLECs was associated with recruitment of VEGF-C\u2013producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk involving iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes.<\/jats:p>","DOI":"10.1084\/jem.20220741","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T02:20:55Z","timestamp":1672971655000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":95,"title":["Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7186-7256","authenticated-orcid":true,"given":"Milena","family":"Petkova","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, Genetics and Pathology, Uppsala University 1 , Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3523-7003","authenticated-orcid":true,"given":"Marle","family":"Kraft","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, Genetics and Pathology, Uppsala University 1 , Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4299-4934","authenticated-orcid":true,"given":"Simon","family":"Stritt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, Genetics and Pathology, Uppsala University 1 , Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9194-2412","authenticated-orcid":true,"given":"Ines","family":"Martinez-Corral","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, Genetics and Pathology, Uppsala University 1 , Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4046-4702","authenticated-orcid":true,"given":"Henrik","family":"Orts\u00e4ter","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, Genetics and Pathology, Uppsala University 1 , Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0709-7808","authenticated-orcid":true,"given":"Michael","family":"Vanlandewijck","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, Genetics and Pathology, Uppsala University 1 , Uppsala, Sweden"},{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine Huddinge, Karolinska Institutet 2 , , Huddinge, Sweden"},{"name":"Campus Flemingsberg, Neo 2 , , Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2339-5928","authenticated-orcid":true,"given":"Bojana","family":"Jakic","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, Genetics and Pathology, Uppsala University 1 , Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1086-8439","authenticated-orcid":true,"given":"Eul\u00e0lia","family":"Baselga","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hospital Sant Joan de D\u00e9u 3 , Esplugues de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7007-3155","authenticated-orcid":true,"given":"Sandra D.","family":"Castillo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00btzwk36","id-type":"ROR","asserted-by":"publisher"}],"name":"Endothelial Pathobiology and Microenvironment Group, Josep Carreras Leukaemia Research Institute (IJC) 4 , Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4608-4185","authenticated-orcid":true,"given":"Mariona","family":"Graupera","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00btzwk36","id-type":"ROR","asserted-by":"publisher"}],"name":"Endothelial Pathobiology and Microenvironment Group, Josep Carreras Leukaemia Research Institute (IJC) 4 , Badalona, Spain"},{"name":"5CIBERONC, Instituto de Salud Carlos III, Madrid, Spain"},{"name":"6ICREA, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8494-971X","authenticated-orcid":true,"given":"Christer","family":"Betsholtz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, Genetics and Pathology, Uppsala University 1 , Uppsala, Sweden"},{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine Huddinge, Karolinska Institutet 2 , , Huddinge, Sweden"},{"name":"Campus Flemingsberg, Neo 2 , , Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9338-1257","authenticated-orcid":true,"given":"Taija","family":"M\u00e4kinen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, Genetics and Pathology, Uppsala University 1 , Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"2023012314435974100_bib1","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1016\/j.celrep.2016.09.083","article-title":"Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3","volume":"17","author":"Alishekevitz","year":"2016","journal-title":"Cell Rep."},{"key":"2023012314435974100_bib2","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1038\/s44161-022-00107-8","article-title":"When, where and which PIK3CA mutations are pathogenic in congenital disorders","volume":"1","author":"Angulo-Urarte","year":"2022","journal-title":"Nat. Cardiovasc. Res."},{"key":"2023012314435974100_bib3","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1073\/pnas.0510857103","article-title":"Cancer-specific mutations in PIK3CA are oncogenic in vivo","volume":"103","author":"Bader","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023012314435974100_bib4","doi-asserted-by":"publisher","first-page":"90103","DOI":"10.1172\/jci.insight.90103","article-title":"Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract","volume":"2","author":"Baluk","year":"2017","journal-title":"JCI Insight"},{"key":"2023012314435974100_bib5","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41419-017-0064-x","article-title":"PI3K\/mTOR inhibition promotes the regression of experimental vascular malformations driven by PIK3CA-activating mutations","volume":"9","author":"di Blasio","year":"2018","journal-title":"Cell Death Dis."},{"key":"2023012314435974100_bib6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0200343","article-title":"PIK3CA mutations are specifically localized to lymphatic endothelial cells of lymphatic malformations","volume":"13","author":"Blesinger","year":"2018","journal-title":"PLoS One"},{"key":"2023012314435974100_bib7","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s10456-014-9453-2","article-title":"AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation","volume":"18","author":"Boscolo","year":"2015","journal-title":"Angiogenesis"},{"key":"2023012314435974100_bib8","doi-asserted-by":"publisher","first-page":"1835","DOI":"10.1084\/jem.20110571","article-title":"Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice","volume":"208","author":"Boulday","year":"2011","journal-title":"J. Exp. Med."},{"key":"2023012314435974100_bib9","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1161\/CIRCRESAHA.120.317025","article-title":"Tamoxifen-Activated CreERT impairs retinal angiogenesis independently of gene deletion","volume":"127","author":"Brash","year":"2020","journal-title":"Circ. Res."},{"key":"2023012314435974100_bib10","doi-asserted-by":"publisher","first-page":"8421","DOI":"10.1073\/pnas.1501352112","article-title":"Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice","volume":"112","author":"Bravi","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023012314435974100_bib11","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nbt.4096","article-title":"Integrating single-cell transcriptomic data across different conditions, technologies, and species","volume":"36","author":"Butler","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"2023012314435974100_bib12","doi-asserted-by":"publisher","DOI":"10.1101\/079509","article-title":"SCORPIUS improves trajectory inference and identifies novel modules in dendritic cell development","author":"Cannoodt","year":"2016","journal-title":"bioRxiv"},{"key":"2023012314435974100_bib13","doi-asserted-by":"publisher","first-page":"332ra42","DOI":"10.1126\/scitranslmed.aaf1164","article-title":"Somatic PIK3CA mutations as a driver of sporadic venous malformations","volume":"8","author":"Castel","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"2023012314435974100_bib14","doi-asserted-by":"publisher","first-page":"332ra43","DOI":"10.1126\/scitranslmed.aad9982","article-title":"Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans","volume":"8","author":"Castillo","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"2023012314435974100_bib15","doi-asserted-by":"publisher","first-page":"13587","DOI":"10.1038\/s41598-017-13665-w","article-title":"Controlling for confounding effects in single cell RNA sequencing studies using both control and target genes","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"2023012314435974100_bib16","doi-asserted-by":"publisher","first-page":"39421","DOI":"10.18632\/oncotarget.9820","article-title":"Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation","volume":"7","author":"Christiansen","year":"2016","journal-title":"Oncotarget"},{"key":"2023012314435974100_bib17","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/j.smim.2016.10.012","article-title":"Innate immunity, hemostasis and matrix remodeling: PTX3 as a link","volume":"28","author":"Doni","year":"2016","journal-title":"Semin. Immunol."},{"key":"2023012314435974100_bib18","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.ccr.2013.01.023","article-title":"Selective requirement of PI3K\/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer","volume":"23","author":"Eser","year":"2013","journal-title":"Cancer Cell"},{"key":"2023012314435974100_bib19","doi-asserted-by":"publisher","first-page":"518","DOI":"10.3389\/fimmu.2019.00518","article-title":"The interplay between lymphatic vessels and chemokines","volume":"10","author":"Farnsworth","year":"2019","journal-title":"Front. Immunol."},{"key":"2023012314435974100_bib20","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1084\/jem.176.5.1477","article-title":"Characterization and cloning of a novel glycoprotein expressed by stromal cells in T-dependent areas of peripheral lymphoid tissues","volume":"176","author":"Farr","year":"1992","journal-title":"J. Exp. Med."},{"key":"2023012314435974100_bib21","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1158\/2326-6066.CIR-20-0784","article-title":"MHC class II antigen presentation by lymphatic endothelial cells in tumors promotes intratumoral regulatory T cell-suppressive functions","volume":"9","author":"Gkountidi","year":"2021","journal-title":"Cancer Immunol. Res."},{"key":"2023012314435974100_bib22","doi-asserted-by":"publisher","DOI":"10.1172\/JCI140685","article-title":"Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation","volume":"132","author":"Glinton","year":"2022","journal-title":"J. Clin. Invest."},{"key":"2023012314435974100_bib23","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1038\/nri1733","article-title":"Monocyte and macrophage heterogeneity","volume":"5","author":"Gordon","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"2023012314435974100_bib24","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/nature06892","article-title":"Angiogenesis selectively requires the p110\u03b1 isoform of PI3K to control endothelial cell migration","volume":"453","author":"Graupera","year":"2008","journal-title":"Nature"},{"key":"2023012314435974100_bib25","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1016\/j.yexcr.2013.02.021","article-title":"Regulation of angiogenesis by PI3K signaling networks","volume":"319","author":"Graupera","year":"2013","journal-title":"Exp. Cell Res."},{"key":"2023012314435974100_bib26","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1016\/j.cell.2007.03.051","article-title":"Binding of ras to phosphoinositide 3-kinase p110\u03b1 is required for ras-driven tumorigenesis in mice","volume":"129","author":"Gupta","year":"2007","journal-title":"Cell"},{"key":"2023012314435974100_bib27","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"2023012314435974100_bib28","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/2045-824X-4-15","article-title":"Deciphering the roles of macrophages in developmental and inflammation stimulated lymphangiogenesis","volume":"4","author":"Harvey","year":"2012","journal-title":"Vasc. Cell"},{"key":"2023012314435974100_bib29","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020107192","article-title":"Transcription factor FOXP2 is a flow-induced regulator of collecting lymphatic vessels","volume":"40","author":"Hern\u00e1ndez V\u00e1squez","year":"2021","journal-title":"EMBO J."},{"key":"2023012314435974100_bib30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0162532","article-title":"Signaling of prostaglandin E receptors, EP3 and EP4 Facilitates wound healing and lymphangiogenesis with enhanced recruitment of M2 macrophages in mice","volume":"11","author":"Hosono","year":"2016","journal-title":"PLoS One"},{"key":"2023012314435974100_bib31","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/s41590-022-01158-6","article-title":"Neuroinflammation creates an immune regulatory niche at the meningeal lymphatic vasculature near the cribriform plate","volume":"23","author":"Hsu","year":"2022","journal-title":"Nat. Immunol."},{"key":"2023012314435974100_bib32","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2019-0319","article-title":"Celecoxib as a potential treatment for intractable lymphatic malformation","volume":"144","author":"Imamura","year":"2019","journal-title":"Pediatrics"},{"key":"2023012314435974100_bib33","first-page":"111","article-title":"Induction of cyclooxygenase-2 on activated T lymphocytes: Regulation of T cell activation by cyclooxygenase-2 inhibitors","volume":"163","author":"I\u00f1iguez","year":"1999","journal-title":"J. Immunol. Baltim. Md."},{"key":"2023012314435974100_bib34","doi-asserted-by":"publisher","first-page":"514","DOI":"10.3389\/fimmu.2014.00514","article-title":"From monocytes to M1\/M2 macrophages: Phenotypical vs. Functional differentiation","volume":"5","author":"Italiani","year":"2014","journal-title":"Front. Immunol."},{"key":"2023012314435974100_bib35","doi-asserted-by":"publisher","first-page":"4916","DOI":"10.1038\/s41598-017-04982-1","article-title":"Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1","volume":"7","author":"Jha","year":"2017","journal-title":"Sci. Rep."},{"key":"2023012314435974100_bib36","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1038\/labinvest.2011.84","article-title":"Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema","volume":"91","author":"Kashiwagi","year":"2011","journal-title":"Lab. Invest."},{"key":"2023012314435974100_bib37","doi-asserted-by":"publisher","first-page":"5650","DOI":"10.1182\/blood-2008-09-176776","article-title":"Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution","volume":"113","author":"Kataru","year":"2009","journal-title":"Blood"},{"key":"2023012314435974100_bib38","doi-asserted-by":"publisher","first-page":"2316","DOI":"10.1172\/JCI26354","article-title":"The crucial role of macrophages in lymphangiogenesis","volume":"115","author":"Kerjaschki","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2023012314435974100_bib39","doi-asserted-by":"publisher","first-page":"R36","DOI":"10.1186\/gb-2013-14-4-r36","article-title":"TopHat2: Accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions","volume":"14","author":"Kim","year":"2013","journal-title":"Genome Biol."},{"key":"2023012314435974100_bib40","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1089\/lrb.2010.0018","article-title":"Tertiary lymphoid organs in lymphatic malformations","volume":"9","author":"Kirsh","year":"2011","journal-title":"Lymphat. Res. Biol."},{"key":"2023012314435974100_bib41","doi-asserted-by":"publisher","DOI":"10.1101\/2021.07.16.452617","article-title":"Low dose AKT inhibitor miransertib cures PI3K-related vascular malformations in preclinical models of human disease.","author":"Kobialka","year":"2021"},{"key":"2023012314435974100_bib42","doi-asserted-by":"publisher","DOI":"10.1172\/JCI155478","article-title":"Lymphangiogenesis requires Ang2\/Tie\/PI3K signaling for VEGFR3 cell-surface expression","volume":"132","author":"Korhonen","year":"2022","journal-title":"J. Clin. Invest."},{"key":"2023012314435974100_bib43","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"2023012314435974100_bib44","doi-asserted-by":"publisher","first-page":"3057","DOI":"10.1084\/jem.20180654","article-title":"IFN\u03b3-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin","volume":"215","author":"Lane","year":"2018","journal-title":"J. Exp. Med."},{"key":"2023012314435974100_bib45","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1158\/0008-5472.CAN-08-1565","article-title":"Low levels of tumor necrosis factor alpha increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site","volume":"69","author":"Li","year":"2009","journal-title":"Cancer Res."},{"key":"2023012314435974100_bib46","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"2023012314435974100_bib47","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1016\/j.ajhg.2015.11.011","article-title":"Somatic activating PIK3CA mutations cause venous malformation","volume":"97","author":"Limaye","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"2023012314435974100_bib48","doi-asserted-by":"publisher","first-page":"36","DOI":"10.3389\/fimmu.2019.00036","article-title":"Lymph node lymphatic endothelial cell expansion and contraction and the programming of the immune response","volume":"10","author":"Lucas","year":"2019","journal-title":"Front. Immunol."},{"key":"2023012314435974100_bib49","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1016\/j.jpeds.2014.12.069","article-title":"Lymphatic and other vascular malformative\/overgrowth disorders are caused by somatic mutations in PIK3CA","volume":"166","author":"Luks","year":"2015","journal-title":"J. Pediatr."},{"key":"2023012314435974100_bib50","doi-asserted-by":"publisher","first-page":"2938","DOI":"10.3389\/fimmu.2019.02938","article-title":"Chronic inflammation: A common promoter in tertiary lymphoid organ neogenesis","volume":"10","author":"Luo","year":"2019","journal-title":"Front. Immunol."},{"key":"2023012314435974100_bib51","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1593\/neo.111570","article-title":"Rapamycin inhibits lymphatic endothelial cell tube formation by downregulating vascular endothelial growth factor receptor 3 protein expression","volume":"14","author":"Luo","year":"2012","journal-title":"Neoplasia"},{"key":"2023012314435974100_bib52","doi-asserted-by":"publisher","first-page":"3901","DOI":"10.1172\/JCI73777","article-title":"Cyclooxygenase-2-dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer","volume":"124","author":"Lyons","year":"2014","journal-title":"J. Clin. Invest."},{"key":"2023012314435974100_bib53","doi-asserted-by":"publisher","first-page":"3955","DOI":"10.1182\/blood-2010-02-266296","article-title":"An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation","volume":"116","author":"MacDonald","year":"2010","journal-title":"Blood"},{"key":"2023012314435974100_bib54","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat. Neurosci."},{"key":"2023012314435974100_bib55","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1016\/j.molmed.2018.08.003","article-title":"Cancer-associated PIK3CA mutations in overgrowth disorders","volume":"24","author":"Madsen","year":"2018","journal-title":"Trends Mol. Med."},{"key":"2023012314435974100_bib56","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1111\/cas.12475","article-title":"Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions","volume":"105","author":"Majumder","year":"2014","journal-title":"Cancer Sci."},{"key":"2023012314435974100_bib57","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1161\/CIRCRESAHA.121.318142","article-title":"Lymphatic malformations: Genetics, mechanisms and therapeutic strategies","volume":"129","author":"M\u00e4kinen","year":"2021","journal-title":"Circ. Res."},{"key":"2023012314435974100_bib58","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1007\/s10456-016-9505-x","article-title":"Vegfr3-CreER (T2) mouse, a new genetic tool for targeting the lymphatic system","volume":"19","author":"Martinez-Corral","year":"2016","journal-title":"Angiogenesis"},{"key":"2023012314435974100_bib59","doi-asserted-by":"publisher","first-page":"2869","DOI":"10.1038\/s41467-020-16496-y","article-title":"Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation","volume":"11","author":"Martinez-Corral","year":"2020","journal-title":"Nat. Commun."},{"key":"2023012314435974100_bib60","doi-asserted-by":"publisher","DOI":"10.48550\/arXiv.1802.03426","article-title":"UMAP: Uniform manifold approximation and projection for dimension reduction","author":"McInnes","year":"2020","journal-title":"ArXiv"},{"key":"2023012314435974100_bib61","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1002\/dvg.20335","article-title":"A global double-fluorescent Cre reporter mouse","volume":"45","author":"Muzumdar","year":"2007","journal-title":"Genesis"},{"key":"2023012314435974100_bib62","doi-asserted-by":"publisher","first-page":"13650","DOI":"10.1038\/ncomms13650","article-title":"PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia","volume":"7","author":"Ola","year":"2016","journal-title":"Nat. Commun."},{"key":"2023012314435974100_bib63","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1093\/hmg\/ddu505","article-title":"Activating PIK3CA alleles and lymphangiogenic phenotype of lymphatic endothelial cells isolated from lymphatic malformations","volume":"24","author":"Osborn","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2023012314435974100_bib64","doi-asserted-by":"publisher","first-page":"btab209","DOI":"10.1093\/bioinformatics\/btab209","article-title":"ShinyCell: Simple and sharable visualisation of single-cell gene expression data","author":"Ouyang","year":"2021","journal-title":"Bioinformatics"},{"key":"2023012314435974100_bib65","doi-asserted-by":"publisher","first-page":"3487","DOI":"10.1172\/JCI39482","article-title":"Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia","volume":"119","author":"Park","year":"2009","journal-title":"J. Clin. Invest."},{"key":"2023012314435974100_bib66","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/s10456-012-9305-x","article-title":"Neuropilin-2 and vascular endothelial growth factor receptor-3 are up-regulated in human vascular malformations","volume":"16","author":"Partanen","year":"2013","journal-title":"Angiogenesis"},{"key":"2023012314435974100_bib67","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax4063","article-title":"Biological functions of lymphatic vessels","volume":"369","author":"Petrova","year":"2020","journal-title":"Science"},{"key":"2023012314435974100_bib68","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1038\/nmeth.2639","article-title":"Smart-seq2 for sensitive full-length transcriptome profiling in single cells","volume":"10","author":"Picelli","year":"2013","journal-title":"Nat. Methods"},{"key":"2023012314435974100_bib69","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/nprot.2014.006","article-title":"Full-length RNA-seq from single cells using Smart-seq2","volume":"9","author":"Picelli","year":"2014","journal-title":"Nat. Protoc."},{"key":"2023012314435974100_bib70","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1161\/CIRCRESAHA.121.318145","article-title":"Genetic basis and therapies for vascular anomalies","volume":"129","author":"Queisser","year":"2021","journal-title":"Circ. Res."},{"key":"2023012314435974100_bib71","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1084\/jem.20181353","article-title":"Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly","volume":"216","author":"Rodriguez-Laguna","year":"2019","journal-title":"J. Exp. Med."},{"key":"2023012314435974100_bib72","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.3389\/fimmu.2019.01033","article-title":"The antigen processing and presentation machinery in lymphatic endothelial cells","volume":"10","author":"Santambrogio","year":"2019","journal-title":"Front. Immunol."},{"key":"2023012314435974100_bib73","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nbt.3192","article-title":"Spatial reconstruction of single-cell gene expression data","volume":"33","author":"Satija","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"2023012314435974100_bib74","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/S0002-9440(10)64255-1","article-title":"Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis","volume":"161","author":"Schoppmann","year":"2002","journal-title":"Am. J. Pathol."},{"key":"2023012314435974100_bib75","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1016\/j.celrep.2015.02.026","article-title":"cKit lineage hemogenic endothelium-derived cells contribute to mesenteric lymphatic vessels","volume":"10","author":"Stanczuk","year":"2015","journal-title":"Cell Rep."},{"key":"2023012314435974100_bib76","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1186\/s12864-018-4772-0","article-title":"Slingshot: Cell lineage and pseudotime inference for single-cell transcriptomics","volume":"19","author":"Street","year":"2018","journal-title":"BMC Genomics"},{"key":"2023012314435974100_bib77","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"2023012314435974100_bib78","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.immuni.2019.06.027","article-title":"Single-cell survey of human lymphatics unveils marked endothelial cell heterogeneity and mechanisms of homing for neutrophils","volume":"51","author":"Takeda","year":"2019","journal-title":"Immunity"},{"key":"2023012314435974100_bib79","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.3389\/fimmu.2019.01462","article-title":"The metabolic signature of macrophage responses","volume":"10","author":"Viola","year":"2019","journal-title":"Front. Immunol."},{"key":"2023012314435974100_bib80","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1038\/nature09002","article-title":"Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis","volume":"465","author":"Wang","year":"2010","journal-title":"Nature"},{"key":"2023012314435974100_bib81","doi-asserted-by":"publisher","first-page":"52","DOI":"10.3389\/fcvm.2020.00052","article-title":"A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculature","volume":"7","author":"Xiang","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"2023012314435974100_bib82","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0150606","article-title":"A protocol for the comprehensive flow cytometric analysis of immune cells in normal and inflamed murine non-lymphoid tissues","volume":"11","author":"Yu","year":"2016","journal-title":"PLoS One"}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20220741\/1446792\/jem_20220741.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20220741\/1446792\/jem_20220741.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T09:47:30Z","timestamp":1674467250000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/220\/4\/e20220741\/213817\/Immune-interacting-lymphatic-endothelial-subtype"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,23]]},"references-count":82,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4,3]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20220741","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.05.22.492950","asserted-by":"object"}]},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,23]]},"article-number":"e20220741"}}