{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T02:28:43Z","timestamp":1788056923524,"version":"build-2784847793"},"reference-count":198,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Lymphedema is a chronic inflammatory disease without an effective treatment method, and it results in a high disease burden and psychological distress in patients. Although there have been significant advances in targeted therapies, there are still no effective options to treat this refractory disease. In recent years, new advances and breakthroughs have been made in signaling pathways, including RAS\/MAPK, PI3K\/AKT, VEGF-C\/VEGFR-3, HGF\/MET, and TGF-\u03b21, which are important for understanding the pathogenesis and disease progression of lymphedema. Mutations in genes encoding cell junctions affect the formation of junctions in lymphatic endothelial cells (LECs), causing abnormal lymphatic valve development and the impairment of lymphatic vessels. A vicious cycle of oxidative stress and chronic inflammation of lymphatic vessels leads to lymphedema. Moreover, the interactions and information communication of T-cell subsets, neutrophils, macrophages, dendritic cells (DCs), and fibroblasts with LECs play equally important roles in the progression of lymphedema. Therefore, this paper summarizes the reported signaling pathways, cell junctions, oxidative stress, and cell communication involved in lymphedema, with the goal of providing ideas and a basis for understanding the pathogenesis, disease progression and targeted therapy of lymphedema. By integrating current findings on signaling dysregulation, cell junctions, and cellular crosstalk, this review provides a conceptual framework for developing multitarget therapeutic strategies to restore lymphatic homeostasis and develop potential therapies for treating lymphedema.<\/jats:p>","DOI":"10.3389\/fcell.2025.1521320","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T05:31:08Z","timestamp":1753162268000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Characteristics and advances in signaling pathways, cellular communication, cell junctions, and oxidative stress in lymphedema"],"prefix":"10.3389","volume":"13","author":[{"given":"Qiancheng","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipu","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongqi","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiankai","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianshi","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/nrm2183","article-title":"Molecular regulation of angiogenesis and lymphangiogenesis","volume":"8","author":"Adams","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e112548","DOI":"10.1371\/journal.pone.0112548","article-title":"Evidence for SH2 domain-containing 5'-inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction","volume":"9","author":"Agollah","year":"2014","journal-title":"PLoS One"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1093\/hmg\/ddae060","article-title":"Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function","volume":"33","author":"Alpaslan","year":"2024","journal-title":"Hum. Mol. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1128\/CVI.00257-14","article-title":"Interleukin 1 (IL-1)- and IL-23-mediated expansion of filarial antigen-specific Th17 and Th22 cells in filarial lymphedema","volume":"21","author":"Anuradha","year":"2014","journal-title":"Clin. Vaccine Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.ajhg.2010.08.008","article-title":"Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans","volume":"87","author":"Au","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3202","DOI":"10.2353\/ajpath.2010.100594","article-title":"Blockade of transforming growth factor-beta1 accelerates lymphatic regeneration during wound repair","volume":"177","author":"Avraham","year":"2010","journal-title":"Am. J. Pathol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1096\/fj.12-222695","article-title":"Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema","volume":"27","author":"Avraham","year":"2013","journal-title":"FASEB J."},{"key":"B8","doi-asserted-by":"publisher","first-page":"4600","DOI":"10.1128\/IAI.05419-11","article-title":"Filarial lymphatic pathology reflects augmented toll-like receptor-mediated, mitogen-activated protein kinase-mediated proinflammatory cytokine production","volume":"79","author":"Babu","year":"2011","journal-title":"Infect. Immun."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e420","DOI":"10.1371\/journal.pntd.0000420","article-title":"Filarial lymphedema is characterized by antigen-specific Th1 and th17 proinflammatory responses and a lack of regulatory T cells","volume":"3","author":"Babu","year":"2009","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B10","doi-asserted-by":"publisher","first-page":"3248","DOI":"10.4049\/jimmunol.176.5.3248","article-title":"Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence","volume":"176","author":"Babu","year":"2006","journal-title":"J. Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e758","DOI":"10.1002\/ctm2.758","article-title":"TGF-\u03b21 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation","volume":"12","author":"Baik","year":"2022","journal-title":"Clin. Transl. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.1084\/jem.20062596","article-title":"Functionally specialized junctions between endothelial cells of lymphatic vessels","volume":"204","author":"Baluk","year":"2007","journal-title":"J. Exp. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"3315","DOI":"10.1172\/JCI99027","article-title":"Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow","volume":"130","author":"Betterman","year":"2020","journal-title":"J. Clin. Invest"},{"key":"B14","article-title":"The initial lymphatics: new methods and findings: international symposium Zurich 1984","author":"Bollinger","year":"1985"},{"key":"B15","doi-asserted-by":"publisher","first-page":"7414","DOI":"10.3390\/ijms23137414","article-title":"Low efficacy of genetic tests for the diagnosis of primary lymphedema prompts novel insights into the underlying molecular pathways","volume":"23","author":"Bonetti","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1161\/CIRCRESAHA.111.250738","article-title":"CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo","volume":"109","author":"Bos","year":"2011","journal-title":"Circ. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3907","DOI":"10.3390\/ijms25073907","article-title":"The role of inflammation in lymphedema: a narrative review of pathogenesis and opportunities for therapeutic intervention","volume":"25","author":"Bowman","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1372","DOI":"10.1002\/humu.22682","article-title":"RASopathy-associated CBL germline mutations cause aberrant ubiquitylation and trafficking of EGFR","volume":"35","author":"Brand","year":"2014","journal-title":"Hum. Mutat."},{"key":"B19","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1111\/cge.12158","article-title":"A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family","volume":"84","author":"Brice","year":"2013","journal-title":"Clin. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"642","DOI":"10.3390\/biology10070642","article-title":"Hemodynamic responses in lower limb lymphedema patients undergoing physical therapy","volume":"10","author":"Brix","year":"2021","journal-title":"Biol. (Basel)."},{"key":"B21","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1172\/JCI71614","article-title":"Genetics of lymphatic anomalies","volume":"124","author":"Brouillard","year":"2014","journal-title":"J. Clin. Invest"},{"key":"B22","doi-asserted-by":"publisher","first-page":"4095","DOI":"10.1093\/hmg\/ddx297","article-title":"Loss of ADAMTS3 activity causes hennekam lymphangiectasia-lymphedema syndrome 3","volume":"26","author":"Brouillard","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"B23","doi-asserted-by":"publisher","first-page":"597374","DOI":"10.3389\/fcvm.2020.597374","article-title":"Ras pathways on Prox1 and lymphangiogenesis: insights for therapeutics","volume":"7","author":"Bui","year":"2020","journal-title":"Front. Cardiovasc Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1089\/lrb.2022.0003","article-title":"Adipose tissue in lymphedema: a central feature of pathology and target for pharmacologic therapy","volume":"21","author":"Burton","year":"2023","journal-title":"Lymphat. Res. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.jhep.2018.12.004","article-title":"Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma","volume":"70","author":"Cadamuro","year":"2019","journal-title":"J. Hepatol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1086\/504394","article-title":"Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype","volume":"79","author":"Carta","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1126\/science.aav1444","article-title":"RIT1 oncoproteins escape LZTR1-mediated proteolysis","volume":"363","author":"Castel","year":"2019","journal-title":"Science"},{"key":"B28","first-page":"1343","article-title":"Morphological characteristics of initial lymphatics in the tongue as shown by scanning electron microscopy","author":"Castenholz","year":"1984","journal-title":"Scan Electron Microsc."},{"key":"B29","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1161\/CIRCRESAHA.117.312576","article-title":"Mechanisms of connexin-related lymphedema","volume":"123","author":"Castorena-Gonzalez","year":"2018","journal-title":"Circ. Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1101\/gad.282400.116","article-title":"Mechanotransduction activates canonical Wnt\/\u03b2-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves","volume":"30","author":"Cha","year":"2016","journal-title":"Genes Dev."},{"key":"B31","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1016\/j.celrep.2018.09.049","article-title":"Complementary wnt sources regulate lymphatic vascular development via PROX1-Dependent Wnt\/\u03b2-Catenin signaling","volume":"25","author":"Cha","year":"2018","journal-title":"Cell Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/s1535-6108(02)00033-8","article-title":"Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit","volume":"1","author":"Chan","year":"2002","journal-title":"Cancer Cell"},{"key":"B33","doi-asserted-by":"publisher","first-page":"573","DOI":"10.3109\/13880209.2012.749923","article-title":"The role of cyclooxygenase-derived oxidative stress in surgically induced lymphedema in a mouse tail model","volume":"51","author":"Chang","year":"2013","journal-title":"Pharm. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"524","DOI":"10.7518\/hxkq.2015.05.018","article-title":"Effects of oral cancer-associated fibroblasts on the proliferation, migration, invasion and tube formation to human lymphatic endothelial cells","volume":"33","author":"Chen","year":"2015","journal-title":"Hua Xi Kou Qiang Yi Xue Za Zhi"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e10371","DOI":"10.1002\/btm2.10371","article-title":"Lymphatic channel sheet of polydimethylsiloxane for preventing secondary lymphedema in the rat upper limb model","volume":"8","author":"Cheon","year":"2023","journal-title":"Bioeng. Transl. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/s41598-017-00085-z","article-title":"Hydrolysis of hyaluronic acid in lymphedematous tissue alleviates fibrogenesis via TH1 cell-mediated cytokine expression","volume":"7","author":"Cho","year":"2017","journal-title":"Sci. Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e2","DOI":"10.1161\/CIRCRESAHA.121.320565","article-title":"Piezo1-Regulated mechanotransduction controls flow-activated lymphatic expansion","volume":"131","author":"Choi","year":"2022","journal-title":"Circ. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1158\/0008-5472.CAN-15-1199","article-title":"Aberrant activation of notch signaling inhibits PROX1 activity to enhance the malignant behavior of thyroid cancer cells","volume":"76","author":"Choi","year":"2016","journal-title":"Cancer Res."},{"key":"B39","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":"B40","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/ng.497","article-title":"A restricted spectrum of NRAS mutations causes Noonan syndrome","volume":"42","author":"Cirstea","year":"2010","journal-title":"Nat. Genet."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3109\/09687688.2012.743194","article-title":"An emerging consensus on aquaporin translocation as a regulatory mechanism","volume":"30","author":"Conner","year":"2013","journal-title":"Mol. Membr. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1083\/jcb.201408103","article-title":"Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex","volume":"208","author":"Coon","year":"2015","journal-title":"J. Cell Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1016\/j.jamcollsurg.2017.08.001","article-title":"Vascularized jejunal mesenteric lymph node transfer: a novel surgical treatment for extremity lymphedema","volume":"225","author":"Coriddi","year":"2017","journal-title":"J. Am. Coll. Surg."},{"key":"B44","doi-asserted-by":"publisher","first-page":"5138","DOI":"10.1002\/cncr.25458","article-title":"Lymphedema beyond breast cancer: a systematic review and meta-analysis of cancer-related secondary lymphedema","volume":"116","author":"Cormier","year":"2010","journal-title":"Cancer."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e39558","DOI":"10.1371\/journal.pone.0039558","article-title":"Vascular endothelial growth factor receptor-3 directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis","volume":"7","author":"Coso","year":"2012","journal-title":"PLoS One"},{"key":"B46","doi-asserted-by":"publisher","first-page":"7052","DOI":"10.1074\/jbc.M110.174821","article-title":"Inhibition of proinflammatory RANTES expression by TGF-beta1 is mediated by glycogen synthase kinase-3beta-dependent beta-catenin signaling","volume":"286","author":"Dai","year":"2011","journal-title":"J. Biol. Chem."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e169931","DOI":"10.1172\/jci.insight.169931","article-title":"Connexin-45 is expressed in mouse lymphatic endothelium and required for lymphatic valve function","volume":"9","author":"Davis","year":"2024","journal-title":"JCI Insight"},{"key":"B48","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1146\/annurev-med-060116-022900","article-title":"Lymphedema: pathogenesis and novel therapies","volume":"69","author":"Dayan","year":"2018","journal-title":"Annu. Rev. Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1089\/lrb.2016.0010","article-title":"Pathological changes of lymphedematous skin: increased mast cells, related proteases, and activated transforming growth Factor-\u03b21","volume":"14","author":"Di","year":"2016","journal-title":"Lymphat. Res. Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2806","DOI":"10.1242\/jcs.084186","article-title":"Peripheral lymphangiogenesis in mice depends on ectodermal connexin-26 (Gjb2)","volume":"124","author":"Dicke","year":"2011","journal-title":"J. Cell Sci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/S1470-2045(13)70076-7","article-title":"Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis","volume":"14","author":"DiSipio","year":"2013","journal-title":"Lancet Oncol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.devcel.2021.01.018","article-title":"Beyond PROX1: transcriptional, epigenetic, and noncoding RNA regulation of lymphatic identity and function","volume":"56","author":"Ducoli","year":"2021","journal-title":"Dev. Cell"},{"key":"B53","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s12881-015-0239-1","article-title":"Mutation in NRAS in familial noonan syndrome--case report and review of the literature","volume":"16","author":"Ekvall","year":"2015","journal-title":"BMC Med. Genet."},{"key":"B54","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1023\/a:1023330206021","article-title":"Axilla surgery severely affects quality of life: results of a 5-year prospective study in breast cancer patients","volume":"79","author":"Engel","year":"2003","journal-title":"Breast Cancer Res. Treat."},{"key":"B55","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1111\/j.1749-6632.2002.tb04866.x","article-title":"Research perspectives in inherited lymphatic disease","volume":"979","author":"Ferrell","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B56","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/j.ajhg.2010.04.010","article-title":"GJC2 missense mutations cause human lymphedema","volume":"86","author":"Ferrell","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.3390\/jcm9051550","article-title":"Prevalence and correlates of lymphatic filariasis infection and its morbidity following mass ivermectin and albendazole administration in mkinga district, north-eastern Tanzania","volume":"9","author":"Fimbo","year":"2020","journal-title":"J. Clin. Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"2382","DOI":"10.1158\/1078-0432.CCR-11-2303","article-title":"Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment","volume":"18","author":"Finegold","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"B59","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1089\/lrb.2008.1524","article-title":"HGF and MET mutations in primary and secondary lymphedema","volume":"6","author":"Finegold","year":"2008","journal-title":"Lymphat. Res. Biol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"8085","DOI":"10.1038\/ncomms9085","article-title":"Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune Hydrops fetalis","volume":"6","author":"Fotiou","year":"2015","journal-title":"Nat. Commun."},{"key":"B61","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1172\/JCI33302","article-title":"Adrenomedullin signaling is necessary for murine lymphatic vascular development","volume":"118","author":"Fritz-Six","year":"2008","journal-title":"J. Clin. Invest"},{"key":"B62","doi-asserted-by":"publisher","first-page":"e0239517","DOI":"10.1371\/journal.pone.0239517","article-title":"Short-term molecular and cellular effects of ischemia\/reperfusion on vascularized lymph node flaps in rats","volume":"15","author":"Frueh","year":"2020","journal-title":"PLoS One"},{"key":"B63","doi-asserted-by":"publisher","first-page":"2267","DOI":"10.1084\/jem.20150718","article-title":"Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin","volume":"212","author":"Frye","year":"2015","journal-title":"J. Exp. Med."},{"key":"B64","doi-asserted-by":"publisher","first-page":"e57732","DOI":"10.7554\/eLife.57732","article-title":"EphrinB2-EphB4 signalling provides rho-mediated homeostatic control of lymphatic endothelial cell junction integrity","volume":"9","author":"Frye","year":"2020","journal-title":"Elife"},{"key":"B65","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1089\/lrb.2023.0002","article-title":"The function of T cell immunity in lymphedema: a comprehensive review","volume":"21","author":"Fu","year":"2023","journal-title":"Lymphat. Res. Biol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"e140853","DOI":"10.1172\/JCI140853","article-title":"Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor-mediated lymphangiogenesis","volume":"131","author":"Furlong-Silva","year":"2021","journal-title":"J. Clin. Invest"},{"key":"B67","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.imlet.2016.03.008","article-title":"Pro-lymphangiogenic properties of IFN-\u03b3-activated human dendritic cells","volume":"173","author":"Gagliostro","year":"2016","journal-title":"Immunol. Lett."},{"key":"B68","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":"B69","doi-asserted-by":"publisher","first-page":"R239","DOI":"10.1093\/hmg\/ddg288","article-title":"PTEN: tumour suppressor, multifunctional growth regulator and more","volume":"12","author":"Goberdhan","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"B70","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1002\/humu.22223","article-title":"FLT4\/VEGFR3 and milroy disease: novel mutations, a review of published variants and database update","volume":"34","author":"Gordon","year":"2013","journal-title":"Hum. Mutat."},{"key":"B71","doi-asserted-by":"publisher","first-page":"e89081","DOI":"10.1172\/jci.insight.89081","article-title":"Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function","volume":"1","author":"Gousopoulos","year":"","journal-title":"JCI Insight"},{"key":"B72","doi-asserted-by":"publisher","first-page":"2193","DOI":"10.1016\/j.ajpath.2016.04.006","article-title":"Prominent lymphatic vessel hyperplasia with progressive dysfunction and distinct immune cell infiltration in lymphedema","volume":"186","author":"Gousopoulos","year":"","journal-title":"Am. J. Pathol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1016\/j.jaad.2017.03.022","article-title":"Lymphedema: pathophysiology and clinical manifestations","volume":"77","author":"Grada","year":"2017","journal-title":"J. Am. Acad. Dermatol"},{"key":"B74","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1161\/CIRCULATIONAHA.124.072093","article-title":"Targeting uPARAP modifies lymphatic vessel architecture and attenuates lymphedema","volume":"151","author":"Gucciardo","year":"2025","journal-title":"Circulation"},{"key":"B75","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.annder.2010.03.027","article-title":"Lymphedema and neutrophilic dermatosis","volume":"137","author":"Guyot-Caquelin","year":"2010","journal-title":"Ann. Dermatol Venereol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"23","DOI":"10.3390\/biomedicines6010023","article-title":"GJA4\/Connexin 37 mutations correlate with secondary lymphedema following surgery in breast cancer patients","volume":"6","author":"Hadizadeh","year":"2018","journal-title":"Biomedicines"},{"key":"B77","doi-asserted-by":"publisher","first-page":"e98271","DOI":"10.15252\/embj.201798271","article-title":"Distinct roles of VE-cadherin for development and maintenance of specific lymph vessel beds","volume":"37","author":"H\u00e4gerling","year":"2018","journal-title":"EMBO J."},{"key":"B78","doi-asserted-by":"publisher","first-page":"424","DOI":"10.3390\/cells13050424","article-title":"CD112 supports lymphatic migration of human dermal dendritic cells","volume":"13","author":"Haghayegh Jahromi","year":"2024","journal-title":"Cells"},{"key":"B79","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1002\/ajmg.a.36375","article-title":"Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23","author":"Hanson","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"B80","doi-asserted-by":"publisher","first-page":"e20201776","DOI":"10.1084\/jem.20201776","article-title":"Macroautophagy in lymphatic endothelial cells inhibits T cell-mediated autoimmunity","volume":"218","author":"Harl\u00e9","year":"2021","journal-title":"J. Exp. Med."},{"key":"B81","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1038\/ng1642","article-title":"Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity","volume":"37","author":"Harvey","year":"2005","journal-title":"Nat. Genet."},{"key":"B82","doi-asserted-by":"publisher","first-page":"841641","DOI":"10.3389\/fimmu.2022.841641","article-title":"Lymph leakage promotes immunosuppression by enhancing anti-inflammatory macrophage polarization","volume":"13","author":"Herrada","year":"2022","journal-title":"Front. Immunol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1093\/intimm\/dxaa078","article-title":"IL-6 in inflammation, autoimmunity and cancer","volume":"33","author":"Hirano","year":"2021","journal-title":"Int. Immunol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.1086\/375614","article-title":"Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia","volume":"72","author":"Irrthum","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"B85","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1086\/303019","article-title":"Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase","volume":"67","author":"Irrthum","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"B86","doi-asserted-by":"publisher","first-page":"112777","DOI":"10.1016\/j.celrep.2023.112777","article-title":"VEGFR3 is required for button junction formation in lymphatic vessels","volume":"42","author":"Jannaway","year":"2023","journal-title":"Cell Rep."},{"key":"B87","doi-asserted-by":"publisher","first-page":"27168","DOI":"10.1074\/jbc.274.38.27168","article-title":"90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1","volume":"274","author":"Jensen","year":"1999","journal-title":"J. Biol. Chem."},{"key":"B88","doi-asserted-by":"publisher","first-page":"2359","DOI":"10.2174\/092986707781745541","article-title":"Lymphatic endothelial cells, inflammatory lymphangiogenesis, and prospective players","volume":"14","author":"Ji","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"B89","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.ydbio.2011.04.004","article-title":"Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax","volume":"354","author":"Kanady","year":"2011","journal-title":"Dev. Biol."},{"key":"B90","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.ydbio.2015.06.004","article-title":"Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling","volume":"405","author":"Kanady","year":"2015","journal-title":"Dev. Biol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/75997","article-title":"Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema","volume":"25","author":"Karkkainen","year":"2000","journal-title":"Nat. Genet."},{"key":"B92","doi-asserted-by":"publisher","first-page":"12677","DOI":"10.1073\/pnas.221449198","article-title":"A model for gene therapy of human hereditary lymphedema","volume":"98","author":"Karkkainen","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B93","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1093\/hmg\/ddt518","article-title":"Arap3 is dysregulated in a mouse model of hypotrichosis-lymphedema-telangiectasia and regulates lymphatic vascular development","volume":"23","author":"Kartopawiro","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"B94","doi-asserted-by":"publisher","first-page":"eabc0836","DOI":"10.1126\/scisignal.abc0836","article-title":"Lymphatic-specific intracellular modulation of receptor tyrosine kinase signaling improves lymphatic growth and function","volume":"14","author":"Kataru","year":"2021","journal-title":"Sci. Signal"},{"key":"B95","doi-asserted-by":"publisher","first-page":"2979","DOI":"10.1172\/JCI78888","article-title":"GATA2 is required for lymphatic vessel valve development and maintenance","volume":"125","author":"Kazenwadel","year":"2015","journal-title":"J. Clin. Invest"},{"key":"B96","doi-asserted-by":"publisher","first-page":"2034","DOI":"10.1038\/s41467-017-02247-z","article-title":"Migratory dendritic cells acquire and present lymphatic endothelial cell-archived antigens during lymph node contraction","volume":"8","author":"Kedl","year":"2017","journal-title":"Nat. Commun."},{"key":"B97","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/j.breast.2012.01.013","article-title":"Factors associated with long-term functional outcomes and psychological sequelae in women after breast cancer","volume":"21","author":"Khan","year":"2012","journal-title":"Breast"},{"key":"B98","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1161\/CIRCULATIONAHA.123.064181","article-title":"Abnormal lymphatic Sphingosine-1-Phosphate signaling aggravates lymphatic dysfunction and tissue inflammation","volume":"148","author":"Kim","year":"2023","journal-title":"Circulation"},{"key":"B99","doi-asserted-by":"publisher","first-page":"5464","DOI":"10.3390\/ijms25105464","article-title":"A HGF mutation in the familial case of primary lymphedema: a report","volume":"25","author":"Koksharova","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B100","doi-asserted-by":"publisher","first-page":"e155478","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":"B101","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/s1097-2765(02)00434-3","article-title":"Identification of ARAP3, a novel PI3K effector regulating both arf and rho GTPases, by selective capture on phosphoinositide affinity matrices","volume":"9","author":"Krugmann","year":"2002","journal-title":"Mol. Cell."},{"key":"B102","doi-asserted-by":"publisher","first-page":"68","DOI":"10.3390\/cells13010068","article-title":"Dysregulation of lymphatic endothelial VEGFR3 signaling in disease","volume":"13","author":"Kuonqui","year":"2023","journal-title":"Cells"},{"key":"B103","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1038\/ng863","article-title":"Haploinsufficiency of NSD1 causes Sotos syndrome","volume":"30","author":"Kurotaki","year":"2002","journal-title":"Nat. Genet."},{"key":"B104","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1007\/s10555-018-9734-0","article-title":"Roles of prostaglandins in tumor-associated lymphangiogenesis with special reference to breast cancer","volume":"37","author":"Lala","year":"2018","journal-title":"Cancer Metastasis Rev."},{"key":"B105","first-page":"1863","article-title":"The structure of lymphatic capillaries in lymph formation","volume":"35","author":"Leak","year":"1976","journal-title":"Fed. Proc."},{"key":"B106","doi-asserted-by":"publisher","first-page":"e2308941120","DOI":"10.1073\/pnas.2308941120","article-title":"A 3D biomimetic model of lymphatics reveals cell-cell junction tightening and lymphedema via a cytokine-induced ROCK2\/JAM-A complex","volume":"120","author":"Lee","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B107","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1182\/blood-2008-03-145789","article-title":"Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate","volume":"113","author":"Lee","year":"2009","journal-title":"Blood"},{"key":"B108","doi-asserted-by":"publisher","first-page":"3938","DOI":"10.1016\/j.bjps.2022.08.011","article-title":"Phase 1 lymfactin\u00ae study: 24-Month efficacy and safety results of combined adenoviral VEGF-C and lymph node transfer treatment for upper extremity lymphedema","volume":"75","author":"Lepp\u00e4puska","year":"2022","journal-title":"J. Plast. Reconstr. Aesthet. Surg."},{"key":"B109","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1172\/JCI15650","article-title":"What does Stat3 do?","volume":"109","author":"Levy","year":"2002","journal-title":"J. Clin. Invest"},{"key":"B110","doi-asserted-by":"publisher","first-page":"133061","DOI":"10.1016\/j.ijbiomac.2024.133061","article-title":"An arabinogalactan isolated from Cynanchum atratum promotes lymphangiogenesis and lymphatic vessel remodeling to alleviate secondary lymphedema","volume":"273","author":"Li","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.semcdb.2014.11.012","article-title":"Lymphatic system: an active pathway for immune protection","volume":"38","author":"Liao","year":"2015","journal-title":"Semin. Cell Dev. Biol."},{"key":"B112","doi-asserted-by":"publisher","first-page":"952104","DOI":"10.3389\/fimmu.2022.952104","article-title":"Secreted filarial nematode galectins modulate host immune cells","volume":"13","author":"Loghry","year":"2022","journal-title":"Front. Immunol."},{"key":"B113","doi-asserted-by":"publisher","first-page":"104","DOI":"10.3390\/jfb14020104","article-title":"A novel dressing composed of adipose stem cells and decellularized wharton's jelly facilitated wound healing and relieved lymphedema by enhancing angiogenesis and lymphangiogenesis in a rat model","volume":"14","author":"Lu","year":"2023","journal-title":"J. Funct. Biomater."},{"key":"B114","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1089\/lrb.2007.5102","article-title":"The primary valves in the initial lymphatics during inflammation","volume":"5","author":"Lynch","year":"2007","journal-title":"Lymphat. Res. Biol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"dev184218","DOI":"10.1242\/dev.184218","article-title":"GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through miR-126","volume":"146","author":"Mahamud","year":"2019","journal-title":"Development"},{"key":"B116","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1002\/humu.10129","article-title":"PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13","volume":"20","author":"Maheshwari","year":"2002","journal-title":"Hum. Mutat."},{"key":"B117","volume-title":"The fractal geometry of nature","author":"Mandelbrot","year":"1982"},{"key":"B118","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.1002\/ajmg.a.33445","article-title":"Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases","author":"Mansour","year":"2010","journal-title":"Am. J. Med. Genet. A"},{"key":"B119","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.ajhg.2010.06.015","article-title":"Heterozygous germline mutations in the CBL tumor-suppressor gene cause a noonan syndrome-like phenotype","volume":"87","author":"Martinelli","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"B120","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1002\/ajmg.a.37535","article-title":"Sotos syndrome: an unusual presentation with intrauterine growth restriction, generalized lymphedema, and intention tremor","author":"McClelland","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"B121","doi-asserted-by":"publisher","first-page":"934","DOI":"10.3390\/biology10090934","article-title":"Pilot study of Anti-Th2 immunotherapy for the treatment of breast cancer-related upper extremity lymphedema","volume":"10","author":"Mehrara","year":"2021","journal-title":"Biology"},{"key":"B122","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.3390\/genes11111361","article-title":"Segregation analysis of rare NRP1 and NRP2 variants in families with lymphedema","volume":"11","author":"Michelini","year":"2020","journal-title":"Genes (Basel)"},{"key":"B123","doi-asserted-by":"publisher","first-page":"e1529","DOI":"10.1002\/mgg3.1529","article-title":"NOTCH1: review of its role in lymphatic development and study of seven families with rare pathogenic variants","volume":"9","author":"Michelini","year":"2021","journal-title":"Mol. Genet. Genomic Med."},{"key":"B124","doi-asserted-by":"publisher","first-page":"e66","DOI":"10.1161\/ATVBAHA.122.317781","article-title":"Hypercholesterolemic dysregulation of calpain in lymphatic endothelial cells interferes with regulatory T-Cell stability and trafficking","volume":"43","author":"Miyazaki","year":"2023","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B125","first-page":"121","article-title":"Lymphodysplasia and kras mutation: a case report and literature review","volume":"48","author":"Morcaldi","year":"2015","journal-title":"Lymphology"},{"key":"B126","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1093\/hmg\/ddy412","article-title":"Dominant noonan syndrome-causing LZTR1 mutations specifically affect the kelch domain substrate-recognition surface and enhance RAS-MAPK signaling","volume":"28","author":"Motta","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"B127","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1093\/bjd\/ljad310","article-title":"Self-care treatment for lymphoedema of lymphatic filariasis using integrative medicine","volume":"190","author":"Narahari","year":"2023","journal-title":"Br. J. Dermatol"},{"key":"B128","doi-asserted-by":"publisher","first-page":"157","DOI":"10.2458\/lymph.4668","article-title":"Morbidity management and disability prevention: an agenda for developing nations initiated in India","volume":"53","author":"Narahari","year":"2020","journal-title":"Lymphology"},{"key":"B129","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1016\/j.mucimm.2024.05.003","article-title":"LECs regulate neutrophil clearance through IL-17RC\/CMTM4\/NF-\u03baB axis at sites of inflammation or infection","volume":"17","author":"Ni","year":"2024","journal-title":"Mucosal Immunol."},{"key":"B130","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1083\/jcb.200901104","article-title":"FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1","volume":"185","author":"Norrm\u00e9n","year":"2009","journal-title":"J. Cell Biol."},{"key":"B131","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/BF00218204","article-title":"Three-dimensional organization of lymphatics and its relationship to blood vessels in rat small intestine","volume":"248","author":"Ohtani","year":"1987","journal-title":"Cell Tissue Res."},{"key":"B132","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1146\/annurev.cellbio.21.012704.132338","article-title":"The lymphatic vasculature: recent progress and paradigms","volume":"21","author":"Oliver","year":"2005","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"B133","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1136\/jmg.2010.085563","article-title":"Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype","volume":"48","author":"Ostergaard","year":"2011","journal-title":"J. Med. Genet."},{"key":"B134","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.ajhg.2011.12.018","article-title":"Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy","volume":"90","author":"Ostergaard","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"B135","doi-asserted-by":"publisher","first-page":"965","DOI":"10.3390\/ijms18050965","article-title":"Aged lymphatic vessels and mast cells in perilymphatic tissues","volume":"18","author":"Pal","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B136","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.coi.2018.05.004","article-title":"Dendritic cells, T cells and lymphatics: dialogues in migration and beyond","volume":"53","author":"Permanyer","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"B137","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1111\/j.1365-3024.2009.01133.x","article-title":"Filariasis and lymphoedema","volume":"31","author":"Pfarr","year":"2009","journal-title":"Parasite Immunol."},{"key":"B138","doi-asserted-by":"publisher","first-page":"2176","DOI":"10.1038\/s41467-022-29930-0","article-title":"PD-L1 signaling selectively regulates T cell lymphatic transendothelial migration","volume":"13","author":"Piao","year":"2022","journal-title":"Nat. Commun."},{"key":"B139","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1016\/j.celrep.2019.12.083","article-title":"Regulatory T cells condition lymphatic endothelia for enhanced transendothelial migration","volume":"30","author":"Piao","year":"2020","journal-title":"Cell Rep."},{"key":"B140","first-page":"665","article-title":"Upper limb function and quality of life in breast cancer related lymphedema: a cross-sectional study","volume":"49","author":"Pinto","year":"2013","journal-title":"Eur. J. Phys. Rehabil. Med."},{"key":"B141","doi-asserted-by":"publisher","first-page":"1732","DOI":"10.1161\/ATVBAHA.117.309818","article-title":"Dachsous1-Fat4 signaling controls endothelial cell polarization during lymphatic valve morphogenesis-brief report","volume":"37","author":"Pujol","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B142","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/ng1926","article-title":"Germline gain-of-function mutations in SOS1 cause Noonan syndrome","volume":"39","author":"Roberts","year":"2007","journal-title":"Nat. Genet."},{"key":"B143","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1007\/s00431-010-1206-7","article-title":"A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency (OL-HED-ID)","volume":"169","author":"Roberts","year":"2010","journal-title":"Eur. J. Pediatr."},{"key":"B144","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41572-019-0072-5","article-title":"Cancer-associated secondary lymphoedema","volume":"5","author":"Rockson","year":"2019","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B145","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.molcel.2006.03.027","article-title":"A phosphatase holoenzyme comprised of Shoc2\/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate raf activity","volume":"22","author":"Rodriguez-Viciana","year":"2006","journal-title":"Mol. Cell"},{"key":"B146","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/370527a0","article-title":"Phosphatidylinositol-3-OH kinase as a direct target of ras","volume":"370","author":"Rodriguez-Viciana","year":"1994","journal-title":"Nature"},{"key":"B147","doi-asserted-by":"publisher","first-page":"1189e","DOI":"10.1097\/PRS.0000000000005669","article-title":"Paracrine effects of adipose-derived stem cells promote lymphangiogenesis in irradiated lymphatic endothelial cells","volume":"143","author":"Saijo","year":"2019","journal-title":"Plast. Reconstr. Surg."},{"key":"B148","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1111\/cas.14457","article-title":"Potential role of transforming growth factor-beta 1\/Smad signaling in secondary lymphedema after cancer surgery","volume":"111","author":"Sano","year":"2020","journal-title":"Cancer Sci."},{"key":"B149","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":"B150","doi-asserted-by":"publisher","first-page":"2414","DOI":"10.1016\/j.micinf.2006.05.003","article-title":"Human bancroftian filariasis: immunological markers of morbidity and infection","volume":"8","author":"Satapathy","year":"2006","journal-title":"Microbes Infect."},{"key":"B151","doi-asserted-by":"publisher","first-page":"e0126908","DOI":"10.1371\/journal.pone.0126908","article-title":"Th2 cytokines inhibit lymphangiogenesis","volume":"10","author":"Savetsky","year":"2015","journal-title":"PLoS One"},{"key":"B152","doi-asserted-by":"publisher","first-page":"H165","DOI":"10.1152\/ajpheart.00244.2014","article-title":"Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema","volume":"307","author":"Savetsky","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B153","doi-asserted-by":"publisher","first-page":"a041274","DOI":"10.1101\/cshperspect.a041274","article-title":"Lymphatic vascular permeability","volume":"12","author":"Scallan","year":"2022","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B154","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/nrc2109","article-title":"Hyperactive ras in developmental disorders and cancer","volume":"7","author":"Schubbert","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"B155","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.3390\/ijms24021647","article-title":"TRPML1-Induced lysosomal Ca2+ signals activate AQP2 translocation and water flux in renal collecting duct cells","volume":"24","author":"Scorza","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B156","doi-asserted-by":"publisher","first-page":"894","DOI":"10.3390\/medicina59050894","article-title":"Current concepts in the management of primary lymphedema","volume":"59","author":"Senger","year":"2023","journal-title":"Med. Kaunas."},{"key":"B157","doi-asserted-by":"publisher","first-page":"1472","DOI":"10.1136\/gut.52.10.1472","article-title":"Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells","volume":"52","author":"Sheng","year":"2003","journal-title":"Gut"},{"key":"B158","doi-asserted-by":"publisher","first-page":"e155888","DOI":"10.1172\/jci.insight.155888","article-title":"Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition","volume":"8","author":"Sheppard","year":"2023","journal-title":"JCI Insight"},{"key":"B159","doi-asserted-by":"publisher","first-page":"7774","DOI":"10.3390\/ijms24097774","article-title":"Therapeutic lymphangiogenesis is a promising strategy for secondary lymphedema","volume":"24","author":"Shimizu","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B160","doi-asserted-by":"publisher","first-page":"34757","DOI":"10.1074\/jbc.M113.503946","article-title":"Oral administration of transforming growth factor-\u03b21 (TGF-\u03b21) protects the immature gut from injury via smad protein-dependent suppression of epithelial nuclear factor \u03baB (NF-\u03baB) signaling and proinflammatory cytokine production","volume":"288","author":"Shiou","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B161","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1093\/qjmed\/95.12.803","article-title":"Oxidative stress in chronic lymphoedema","volume":"95","author":"Siems","year":"2002","journal-title":"QJM"},{"key":"B162","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000517605","article-title":"Lymphatic abnormalities in Noonan syndrome spectrum disorders: a systematic review","volume":"13","author":"Sleutjes","year":"2022","journal-title":"Mol. Syndromol."},{"key":"B163","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.cardiores.2003.11.013","article-title":"Gap junctions and the connexin protein family","volume":"62","author":"S\u00f6hl","year":"2004","journal-title":"Cardiovasc Res."},{"key":"B164","doi-asserted-by":"publisher","first-page":"CD009765","DOI":"10.1002\/14651858.CD009765.pub2","article-title":"Conservative interventions for preventing clinically detectable upper-limb lymphoedema in patients who are at risk of developing lymphoedema after breast cancer therapy","volume":"2015","author":"Stuiver","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"B166","doi-asserted-by":"publisher","first-page":"e026889","DOI":"10.1161\/JAHA.122.026889","article-title":"Hydrogen sulfide attenuates lymphedema Via the induction of lymphangiogenesis through a PI3K\/Akt-Dependent mechanism","volume":"11","author":"Suzuki","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"B167","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/s0169-409x(01)00150-8","article-title":"The physiology of the lymphatic system","volume":"50","author":"Swartz","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B168","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1096\/fj.02-0401fje","article-title":"Therapeutic lymphangiogenesis with human recombinant VEGF-C","volume":"16","author":"Szuba","year":"2002","journal-title":"FASEB J."},{"key":"B169","doi-asserted-by":"publisher","first-page":"e254","DOI":"10.1371\/journal.pmed.0030254","article-title":"Inflammatory manifestations of experimental lymphatic insufficiency","volume":"3","author":"Tabibiazar","year":"2006","journal-title":"PLoS Med."},{"key":"B170","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1097\/SAP.0000000000000084","article-title":"Adipose-derived stem cells promote proliferation, migration, and tube formation of lymphatic endothelial cells in vitro by secreting lymphangiogenic factors","volume":"74","author":"Takeda","year":"2015","journal-title":"Ann. plastic Surg."},{"key":"B171","doi-asserted-by":"publisher","first-page":"1458","DOI":"10.1038\/nm1689","article-title":"Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation","volume":"13","author":"Tammela","year":"2007","journal-title":"Nat. Med."},{"key":"B172","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1086\/340847","article-title":"PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity","volume":"70","author":"Tartaglia","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"B173","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/ng772","article-title":"Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome","volume":"29","author":"Tartaglia","year":"2001","journal-title":"Nat. Genet."},{"key":"B174","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1111\/bjd.15238","article-title":"Pathological changes of adipose tissue in secondary lymphoedema","volume":"177","author":"Tashiro","year":"2017","journal-title":"Br. J. Dermatol"},{"key":"B175","doi-asserted-by":"publisher","first-page":"eaal3920","DOI":"10.1126\/scitranslmed.aal3920","article-title":"Leukotriene B4 antagonism ameliorates experimental lymphedema","volume":"9","author":"Tian","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"B176","doi-asserted-by":"publisher","first-page":"e37","DOI":"10.1017\/S1462399408000902","article-title":"Noonan, costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway","volume":"10","author":"Tidyman","year":"2008","journal-title":"Expert Rev. Mol. Med."},{"key":"B177","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/j.gde.2009.04.001","article-title":"The RASopathies: developmental syndromes of Ras\/MAPK pathway dysregulation","volume":"19","author":"Tidyman","year":"2009","journal-title":"Curr. Opin. Genet. Dev."},{"key":"B178","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.mvr.2007.07.005","article-title":"Expression of junctional adhesion molecules on the human lymphatic endothelium","volume":"75","author":"Ueki","year":"2008","journal-title":"Microvasc. Res."},{"key":"B179","doi-asserted-by":"publisher","first-page":"e49229","DOI":"10.1371\/journal.pone.0049229","article-title":"Sotos syndrome is associated with deregulation of the MAPK\/ERK-signaling pathway","volume":"7","author":"Visser","year":"2012","journal-title":"PLoS One"},{"key":"B180","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1113\/jphysiol.2012.247080","article-title":"Lymphatic myogenic constriction - how lymphatic vessels pump lymph uphill","volume":"591","author":"von der Weid","year":"2013","journal-title":"J. Physiol."},{"key":"B181","doi-asserted-by":"publisher","first-page":"e0004917","DOI":"10.1371\/journal.pntd.0004917","article-title":"Evaluating the burden of lymphedema due to lymphatic filariasis in 2005 in khurda district, Odisha state, India","volume":"10","author":"Walsh","year":"2016","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B182","doi-asserted-by":"publisher","first-page":"e2893","DOI":"10.1371\/journal.pntd.0002893","article-title":"Filarial excretory-secretory products induce human monocytes to produce lymphangiogenic mediators","volume":"8","author":"Weinkopff","year":"2014","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B183","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/s0092-8674(00)81511-1","article-title":"Prox1 function is required for the development of the murine lymphatic system","volume":"98","author":"Wigle","year":"1999","journal-title":"Cell"},{"key":"B184","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1055\/a-2322-1325","article-title":"Evidence of modern diagnostic, conservative, and surgical therapy of secondary lymphoedema","volume":"56","author":"Will","year":"","journal-title":"Handchir Mikr"},{"key":"B185","doi-asserted-by":"publisher","first-page":"688e","DOI":"10.1097\/PRS.0000000000011141","article-title":"Lymphedema-associated fibroblasts are related to fibrosis and stage progression in patients and a murine microsurgical model","volume":"154","author":"Will","year":"","journal-title":"Plast. Reconstr. Surg."},{"key":"B186","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.ejvs.2014.10.023","article-title":"Indocyanine green lymphography findings in primary leg lymphedema","volume":"49","author":"Yamamoto","year":"2015","journal-title":"Eur. J. Vasc. Endovasc. Surg."},{"key":"B187","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.2217\/fon.11.121","article-title":"Adipose-derived stem cells promote lymphangiogenesis in response to VEGF-C stimulation or TGF-\u03b21 inhibition","volume":"7","author":"Yan","year":"2011","journal-title":"Future Oncol."},{"key":"B188","doi-asserted-by":"publisher","first-page":"369","DOI":"10.14336\/AD.2023.0420","article-title":"Cancer-associated fibroblasts promote lymphatic metastasis in cholangiocarcinoma via the PDGF-BB\/PDGFR-\u03b2 mediated paracrine signaling network","volume":"15","author":"Yan","year":"2024","journal-title":"Aging Dis."},{"key":"B189","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.21037\/tcr-20-3143","article-title":"Massive limb lymphedema as the initial presentation of multiple myeloma: a case report","volume":"10","author":"Yang","year":"","journal-title":"Transl. Cancer Res."},{"key":"B190","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.3390\/jcm10071540","article-title":"Lymphaticovenous anastomosis supermicrosurgery decreases oxidative stress and increases antioxidant capacity in the serum of lymphedema patients","volume":"10","author":"Yang","year":"","journal-title":"J. Clin. Med."},{"key":"B191","doi-asserted-by":"publisher","first-page":"e0310653","DOI":"10.1371\/journal.pone.0310653","article-title":"TRPML1 acts as a predisposing factor in lymphedema development by regulating the subcellular localization of aquaporin-3, -5","volume":"19","author":"Yang","year":"2024","journal-title":"PLoS One"},{"key":"B192","doi-asserted-by":"publisher","first-page":"2397","DOI":"10.1016\/j.celrep.2019.07.072","article-title":"VE-Cadherin is required for lymphatic valve formation and maintenance","volume":"28","author":"Yang","year":"2019","journal-title":"Cell Rep."},{"key":"B193","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/82_2010_87","article-title":"TGF-\u03b2 function in immune suppression","volume":"350","author":"Yoshimura","year":"2011","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"B194","doi-asserted-by":"publisher","first-page":"E10576","DOI":"10.1073\/pnas.1720352115","article-title":"SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis","volume":"115","author":"Young","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B195","doi-asserted-by":"publisher","first-page":"e49940","DOI":"10.1371\/journal.pone.0049940","article-title":"CD4(+) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis","volume":"7","author":"Zampell","year":"2012","journal-title":"PLoS One"},{"key":"B196","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1089\/lrb.2009.0007","article-title":"Contractile physiology of lymphatics","volume":"7","author":"Zawieja","year":"2009","journal-title":"Lymphat. Res. Biol."},{"key":"B197","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/sj.leu.2403220","article-title":"Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias","volume":"18","author":"Zhao","year":"2004","journal-title":"Leukemia"},{"key":"B198","doi-asserted-by":"publisher","first-page":"171045","DOI":"10.1016\/j.peptides.2023.171045","article-title":"Substance P promote macrophage M2 polarization to attenuate secondary lymphedema by regulating NF-kB\/NLRP3 signaling pathway","volume":"168","author":"Zhou","year":"2023","journal-title":"Peptides"},{"key":"B199","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1126\/science.286.5445.1741","article-title":"Phosphorylation and regulation of raf by akt (protein kinase B)","volume":"286","author":"Zimmermann","year":"1999","journal-title":"Science."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1521320\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T05:31:15Z","timestamp":1753162275000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1521320\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,22]]},"references-count":198,"alternative-id":["10.3389\/fcell.2025.1521320"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2025.1521320","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,22]]},"article-number":"1521320"}}