{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T22:18:00Z","timestamp":1791584280741,"version":"4.3.4"},"reference-count":104,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T00:00:00Z","timestamp":1610582400000},"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>The lymphatic system is essential for lipid absorption\/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance. Despite recent progress toward understanding the cellular and molecular mechanisms underlying the formation of the lymphatic vascular system, the nature of lymphatic vessel abnormalities and disease in humans is complex and poorly understood. The mature lymphatic vasculature forms a hierarchical network in which lymphatic endothelial cells (LECs) are joined by functionally specialized cell-cell junctions to maintain the integrity of lymphatic vessels. Blind-ended and highly permeable lymphatic capillaries drain interstitial fluid via discontinuous, button-like LEC junctions, whereas collecting lymphatic vessels, surrounded by intact basement membranes and lymphatic smooth muscle cells, have continuous, zipper-like LEC junctions to transport lymph to the blood circulatory system without leakage. In this review, we discuss the recent advances in our understanding of the mechanisms by which lymphatic button- and zipper-like junctions play critical roles in lymphatic permeability and function in a tissue- and organ-specific manner, including lacteals of the small intestine. We also provide current knowledge related to key pathways and factors such as VEGF and RhoA\/ROCK signaling that control lymphatic endothelial cell junctional integrity.<\/jats:p>","DOI":"10.3389\/fcell.2020.627647","type":"journal-article","created":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T18:49:00Z","timestamp":1610650140000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Molecular Mechanisms Controlling Lymphatic Endothelial Junction Integrity"],"prefix":"10.3389","volume":"8","author":[{"given":"Pieter R.","family":"Norden","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Kume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1101\/gad.13.3.295","article-title":"Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial\/venous domains, vascular morphogenesis, and sprouting angiogenesis","volume":"13","author":"Adams","year":"1999","journal-title":"Genes Dev"},{"key":"B2","doi-asserted-by":"publisher","first-page":"471","DOI":"10.3390\/cells8050471","article-title":"Role of Angiopoietin-2 in vascular physiology and pathophysiology","volume":"8","author":"Akwii","year":"2019","journal-title":"Cells"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1242\/jcs.116293","article-title":"COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1","volume":"126","author":"Aranguren","year":"2013","journal-title":"J. Cell Sci"},{"key":"B4","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":"B5","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/nrm3721","article-title":"Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration","volume":"15","author":"Barker","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"4572","DOI":"10.1172\/JCI82045","article-title":"DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport","volume":"125","author":"Bernier-Latmani","year":"2015","journal-title":"J. Clin. Invest."},{"key":"B7","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1038\/nrgastro.2017.79","article-title":"Intestinal lymphatic vasculature: structure, mechanisms and functions","volume":"14","author":"Bernier-Latmani","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/bs.apha.2016.04.005","article-title":"Molecular signaling pathways controlling vascular tube morphogenesis and pericyte-induced tube maturation in 3D extracellular matrices","volume":"77","author":"Bowers","year":"2016","journal-title":"Adv. Pharmacol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1136\/jmg.39.7.478","article-title":"Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24","volume":"39","author":"Brice","year":"2002","journal-title":"J. Med. Genet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"C195","DOI":"10.1152\/ajpcell.2000.279.1.C195","article-title":"ROCK mediates thrombin's endothelial barrier dysfunction","volume":"279","author":"Carbajal","year":"2000","journal-title":"Am. J. Physiol. Cell Physiol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1083\/jcb.15.2.259","article-title":"The identification of chylomicra and lipoproteins in tissue sections and their passage into jejunal lacteals","volume":"15","author":"Casley-Smith","year":"1962","journal-title":"J. Cell Biol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.yexcr.2017.06.003","article-title":"Endothelial cell-cell adhesion and signaling","volume":"358","author":"Cerutti","year":"2017","journal-title":"Exp. Cell Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.jcmgh.2018.12.002","article-title":"The intestinal lymphatic system: functions and metabolic implications","volume":"7","author":"Cifarelli","year":"2019","journal-title":"Cell Mol. Gastroenterol. Hepatol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2614","DOI":"10.1182\/blood-2013-12-297317","article-title":"Pressing the right buttons: signaling in lymphangiogenesis","volume":"123","author":"Coso","year":"2014","journal-title":"Blood"},{"key":"B15","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1021\/acsptsci.8b00061","article-title":"Calcitonin-receptor-like receptor signaling governs intestinal lymphatic innervation and lipid uptake","volume":"2","author":"Davis","year":"2019","journal-title":"ACS Pharmacol. Transl. Sci"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e92465","DOI":"10.1172\/jci.insight.92465","article-title":"Lymphatic deletion of calcitonin receptor-like receptor exacerbates intestinal inflammation","volume":"2","author":"Davis","year":"2017","journal-title":"JCI Insight"},{"key":"B17","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.devcel.2009.01.014","article-title":"Transcriptional control of endothelial cell development","volume":"16","author":"De Val","year":"2009","journal-title":"Dev. Cell"},{"key":"B18","doi-asserted-by":"publisher","first-page":"14361","DOI":"10.1038\/ncomms14361","article-title":"The molecular basis of endothelial cell plasticity","volume":"8","author":"Dejana","year":"2017","journal-title":"Nat. Commun"},{"key":"B19","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s00441-008-0694-5","article-title":"Organization and signaling of endothelial cell-to-cell junctions in various regions of the blood and lymphatic vascular trees","volume":"335","author":"Dejana","year":"","journal-title":"Cell Tissue Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.devcel.2009.01.004","article-title":"The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications","volume":"16","author":"Dejana","year":"","journal-title":"Dev. Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.ydbio.2008.04.024","article-title":"Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice","volume":"319","author":"Dellinger","year":"2008","journal-title":"Dev. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"E52","DOI":"10.1111\/j.1749-6632.2010.05716.x","article-title":"Mechanisms of chylomicron uptake into lacteals","volume":"1207","author":"Dixon","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1002\/bit.22337","article-title":"A tissue-engineered model of the intestinal lacteal for evaluating lipid transport by lymphatics","volume":"103","author":"Dixon","year":"2009","journal-title":"Biotechnol. Bioeng"},{"key":"B24","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/s00018-016-2325-8","article-title":"Cell-cell junctional mechanotransduction in endothelial remodeling","volume":"74","author":"Dorland","year":"2017","journal-title":"Cell. Mol. Life Sci"},{"key":"B25","doi-asserted-by":"publisher","first-page":"519","DOI":"10.3389\/fphys.2020.00519","article-title":"Mechanisms ensuring endothelial junction integrity beyond VE-cadherin","volume":"11","author":"Duong","year":"2020","journal-title":"Front. Physiol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1042\/CS20160129","article-title":"Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems","volume":"131","author":"Eklund","year":"2017","journal-title":"Clin. Sci"},{"key":"B27","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1146\/annurev-cellbio-111315-124944","article-title":"Lymphangiogenesis: origin, specification, and cell fate determination","volume":"32","author":"Escobedo","year":"2016","journal-title":"Annu. Rev. Cell Dev. Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1086\/316915","article-title":"Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome","volume":"67","author":"Fang","year":"2000","journal-title":"Am. J. Hum. Genet"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2437","DOI":"10.1172\/JCI80465","article-title":"Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation","volume":"126","author":"Fatima","year":"2016","journal-title":"J. Clin. Invest."},{"key":"B30","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1038\/nature07391","article-title":"Sox18 induces development of the lymphatic vasculature in mice","volume":"456","author":"Francois","year":"2008","journal-title":"Nature"},{"key":"B31","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.ydbio.2011.12.032","article-title":"Segmental territories along the cardinal veins generate lymph sacs via a ballooning mechanism during embryonic lymphangiogenesis in mice","volume":"364","author":"Francois","year":"2012","journal-title":"Dev. Biol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"57732","DOI":"10.7554\/eLife.57732.sa2","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":"B33","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/S1534-5807(02)00217-4","article-title":"Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1","volume":"3","author":"Gale","year":"2002","journal-title":"Dev. Cell"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e137652","DOI":"10.1172\/jci.insight.137652","article-title":"S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress-dependent VEGF-C signaling","volume":"5","author":"Geng","year":"2020","journal-title":"JCI Insight"},{"key":"B35","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/S1097-2765(00)80342-1","article-title":"Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development","volume":"4","author":"Gerety","year":"1999","journal-title":"Mol. Cell"},{"key":"B36","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":"Hagerling","year":"2018","journal-title":"EMBO J"},{"key":"B37","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1038\/emboj.2012.340","article-title":"A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy","volume":"32","author":"Hagerling","year":"2013","journal-title":"EMBO J"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1042\/BST20120103","article-title":"Rho family GTPases","volume":"40","author":"Hall","year":"2012","journal-title":"Biochem. Soc. Trans"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1084\/jem.20181895","article-title":"Lysolipid receptor cross-talk regulates lymphatic endothelial junctions in lymph nodes","volume":"216","author":"Hisano","year":"2019","journal-title":"J. Exp. Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e45261","DOI":"10.1371\/journal.pone.0045261","article-title":"Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice","volume":"7","author":"Hoopes","year":"2012","journal-title":"PLoS ONE"},{"key":"B41","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1242\/jcs.137836","article-title":"FGF2-induced Ras-MAPK signalling maintains lymphatic endothelial cell identity by upregulating endothelial-cell-specific gene expression and suppressing TGFbeta signalling through Smad2","volume":"127","author":"Ichise","year":"2014","journal-title":"J. Cell Sci"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.3389\/fphys.2019.01402","article-title":"The lymphatic system in obesity, insulin resistance, and cardiovascular diseases","volume":"10","author":"Jiang","year":"2019","journal-title":"Front. Physiol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/ni1013","article-title":"Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins","volume":"5","author":"Karkkainen","year":"2004","journal-title":"Nat. Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1002\/dvdy.24313","article-title":"Morphogenesis of the lymphatic vasculature: a focus on new progenitors and cellular mechanisms important for constructing lymphatic vessels","volume":"245","author":"Kazenwadel","year":"2016","journal-title":"Dev. Dyn"},{"key":"B45","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1677\/JOE-06-0045","article-title":"A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats","volume":"192","author":"Kikuchi","year":"2007","journal-title":"J. Endocrinol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"2020","DOI":"10.1002\/dvdy.21200","article-title":"Lymphatic development in mouse small intestine","volume":"236","author":"Kim","year":"2007","journal-title":"Dev. Dyn"},{"key":"B47","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/nature14483","article-title":"Cardiac lymphatics are heterogeneous in origin and respond to injury","volume":"522","author":"Klotz","year":"2015","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1124\/pr.114.009381","article-title":"The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis","volume":"67","author":"Knipe","year":"2015","journal-title":"Pharmacol. Rev"},{"key":"B49","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/978-1-4419-1599-3_5","article-title":"The cooperative roles of Foxc1 and Foxc2 in cardiovascular development,","volume-title":"Forkhead Transcription Factors: Vital Elements in Biology and Medicine, Vol 665","author":"Kume","year":"2009"},{"key":"B50","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/nrc3539","article-title":"Forkhead box proteins: tuning forks for transcriptional harmony","volume":"13","author":"Lam","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"B51","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":"B52","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s00228-011-1100-x","article-title":"Systematic assessment and meta-analysis of the efficacy and safety of fasudil in the treatment of cerebral vasospasm in patients with subarachnoid hemorrhage","volume":"68","author":"Liu","year":"2012","journal-title":"Eur. J. Clin. Pharmacol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"2339","DOI":"10.1084\/jem.20180528","article-title":"hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia","volume":"215","author":"Mackie","year":"2018","journal-title":"J. Exp. Med"},{"key":"B54","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1101\/gad.330105","article-title":"PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature","volume":"19","author":"Makinen","year":"2005","journal-title":"Genes Dev"},{"key":"B55","first-page":"1","article-title":"Lymphedema-distichiasis syndrome,","volume-title":"GeneReviews(R)","author":"Mansour","year":"1993"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1016\/j.yexcr.2013.01.016","article-title":"Regulation of lymphatic vascular morphogenesis: implications for pathological (tumor)lymphangiogenesis","volume":"319","author":"Martinez-Corral","year":"2013","journal-title":"Exp. Cell Res"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1161\/CIRCRESAHA.116.306170","article-title":"Nonvenous origin of dermal lymphatic vasculature","volume":"116","author":"Martinez-Corral","year":"2015","journal-title":"Circ. Res"},{"key":"B58","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.cell.2012.01.013","article-title":"SnapShot: bioactive lysophospholipids","volume":"148","author":"Moolenaar","year":"2012","journal-title":"Cell"},{"key":"B59","doi-asserted-by":"publisher","first-page":"404","DOI":"10.3389\/fphys.2020.00404","article-title":"The role of lymphatic vascular function in metabolic disorders","volume":"11","author":"Norden","year":"2020","journal-title":"Front. Physiol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"e53814","DOI":"10.7554\/eLife.53814.sa2","article-title":"Shear stimulation of FOXC1 and FOXC2 differentially regulates cytoskeletal activity during lymphatic valve maturation","volume":"9","author":"Norden","year":"2020","journal-title":"Elife"},{"key":"B61","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":"Norrmen","year":"2009","journal-title":"J. Cell Biol"},{"key":"B62","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.15252\/emmm.201505731","article-title":"VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption","volume":"7","author":"Nurmi","year":"2015","journal-title":"EMBO Mol. Med"},{"key":"B63","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.cell.2016.02.023","article-title":"The effect of sustained inflammation on hepatic mevalonate pathway results in hyperglycemia","volume":"165","author":"Okin","year":"2016","journal-title":"Cell"},{"key":"B64","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1038\/nm1094","article-title":"Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis","volume":"10","author":"Petrova","year":"2004","journal-title":"Nat. Med"},{"key":"B65","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1084\/jem.20171868","article-title":"Organ-specific lymphatic vasculature: from development to pathophysiology","volume":"215","author":"Petrova","year":"2018","journal-title":"J. Exp. Med"},{"key":"B66","doi-asserted-by":"publisher","first-page":"4063","DOI":"10.1126\/science.aax4063","article-title":"Biological functions of lymphatic vessels","volume":"369","author":"Petrova","year":"2020","journal-title":"Science"},{"key":"B67","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1084\/jem.20091619","article-title":"Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning","volume":"207","author":"Pham","year":"2010","journal-title":"J. Exp. Med"},{"key":"B68","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/nrm.2017.36","article-title":"Vascular heterogeneity and specialization in development and disease","volume":"18","author":"Potente","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1172\/JCI76369","article-title":"Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy","volume":"125","author":"Proia","year":"2015","journal-title":"J. Clin. Invest"},{"key":"B70","doi-asserted-by":"publisher","first-page":"3271","DOI":"10.1007\/s11095-013-1218-x","article-title":"Demonstration of ATP-dependent, transcellular transport of lipid across the lymphatic endothelium using an in vitro model of the lacteal","volume":"30","author":"Reed","year":"2013","journal-title":"Pharm. Res."},{"key":"B71","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/S0962-8924(01)02153-5","article-title":"Rho family proteins: coordinating cell responses","volume":"11","author":"Ridley","year":"2001","journal-title":"Trends Cell Biol"},{"key":"B72","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/S0022-2275(20)41667-0","article-title":"Electron microscopic studies of the assembly, intracellular transport, and secretion of chylomicrons by rat intestine","volume":"18","author":"Sabesin","year":"1977","journal-title":"J. Lipid Res"},{"key":"B73","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.devcel.2011.12.020","article-title":"Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation","volume":"22","author":"Sabine","year":"2012","journal-title":"Dev. Cell"},{"key":"B74","doi-asserted-by":"publisher","first-page":"3861","DOI":"10.1172\/JCI80454","article-title":"FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature","volume":"125","author":"Sabine","year":"2015","journal-title":"J. Clin. Invest"},{"key":"B75","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1038\/nrd.2016.278","article-title":"Therapeutic targeting of the angiopoietin-TIE pathway","volume":"16","author":"Saharinen","year":"2017","journal-title":"Nat. Rev. Drug Discov"},{"key":"B76","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1111\/cge.13148","article-title":"Axenfeld-rieger syndrome","volume":"93","author":"Seifi","year":"2018","journal-title":"Clin. Genet"},{"key":"B77","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1242\/dev.132431","article-title":"Development of the lymphatic system: new questions and paradigms","volume":"143","author":"Semo","year":"2016","journal-title":"Development"},{"key":"B78","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1161\/ATVBAHA.113.302923","article-title":"Genetic dissection of tie pathway in mouse lymphatic maturation and valve development","volume":"34","author":"Shen","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol"},{"key":"B79","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1097\/FJC.0b013e3182a3718f","article-title":"Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil","volume":"62","author":"Shi","year":"2013","journal-title":"J. Cardiovasc. Pharmacol"},{"key":"B80","doi-asserted-by":"publisher","first-page":"571","DOI":"10.3171\/jns.1992.76.4.0571","article-title":"Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial","volume":"76","author":"Shibuya","year":"1992","journal-title":"J. Neurosurg"},{"key":"B81","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1073\/pnas.1714446115","article-title":"Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP","volume":"115","author":"Souma","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B82","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1093\/cvr\/cvq086","article-title":"Role of GTPases in control of microvascular permeability","volume":"87","author":"Spindler","year":"2010","journal-title":"Cardiovasc. Res"},{"key":"B83","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1101\/gad.1859310","article-title":"The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells","volume":"24","author":"Srinivasan","year":"2010","journal-title":"Genes Dev"},{"key":"B84","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1101\/gad.16974811","article-title":"Prox1 dosage controls the number of lymphatic endothelial cell progenitors and the formation of the lymphovenous valves","volume":"25","author":"Srinivasan","year":"2011","journal-title":"Genes Dev"},{"key":"B85","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":"B86","doi-asserted-by":"publisher","first-page":"e46927","DOI":"10.15252\/embr.201846927","article-title":"Gut microbiota regulates lacteal integrity by inducing VEGF-C in intestinal villus macrophages","volume":"20","author":"Suh","year":"2019","journal-title":"EMBO Rep"},{"key":"B87","doi-asserted-by":"publisher","first-page":"e029223","DOI":"10.1101\/cshperspect.a029223","article-title":"Hold me, but not too tight-endothelial cell-cell junctions in angiogenesis","volume":"10","author":"Szymborska","year":"2018","journal-title":"Cold Spring Harb. Perspect. Biol"},{"key":"B88","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1038\/ejhg.2009.93","article-title":"Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations","volume":"17","author":"Tumer","year":"2009","journal-title":"Eur. J. Hum. Genet"},{"key":"B89","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1161\/01.RES.87.4.335","article-title":"Activation of RhoA by thrombin in endothelial hyperpermeability: role of Rho kinase and protein tyrosine kinases","volume":"87","author":"Van Nieuw Amerongen","year":"2000","journal-title":"Circ. Res"},{"key":"B90","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":"B91","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1242\/jcs.114.7.1343","article-title":"Rho and Rac but not Cdc42 regulate endothelial cell permeability","volume":"114","author":"Wojciak-Stothard","year":"2001","journal-title":"J. Cell Sci"},{"key":"B92","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/nature08241","article-title":"A genetically encoded photoactivatable Rac controls the motility of living cells","volume":"461","author":"Wu","year":"2009","journal-title":"Nature"},{"key":"B93","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.3389\/fphys.2019.01604","article-title":"Emerging role of lymphatics in the regulation of intestinal lipid mobilization","volume":"10","author":"Xiao","year":"2019","journal-title":"Front. Physiol"},{"key":"B94","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1111\/j.1365-2443.2008.01279.x","article-title":"COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction","volume":"14","author":"Yamazaki","year":"2009","journal-title":"Genes Cells"},{"key":"B95","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":"B96","doi-asserted-by":"publisher","first-page":"2340","DOI":"10.1182\/blood-2012-05-428607","article-title":"Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos","volume":"120","author":"Yang","year":"2012","journal-title":"Blood"},{"key":"B97","doi-asserted-by":"publisher","first-page":"2561","DOI":"10.1016\/j.ajpath.2012.02.019","article-title":"Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation","volume":"180","author":"Yao","year":"2012","journal-title":"Am. J. Pathol."},{"key":"B98","doi-asserted-by":"publisher","first-page":"e0232356","DOI":"10.1371\/journal.pone.0232356","article-title":"TGF-beta and TNF-alpha cooperatively induce mesenchymal transition of lymphatic endothelial cells via activation of Activin signals","volume":"15","author":"Yoshimatsu","year":"2020","journal-title":"PLoS ONE"},{"key":"B99","doi-asserted-by":"publisher","first-page":"3320","DOI":"10.1167\/iovs.13-13779","article-title":"Role of angiopoietin-2 in corneal lymphangiogenesis","volume":"55","author":"Yuen","year":"2014","journal-title":"Invest. Ophthalmol. Vis. Sci"},{"key":"B100","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1126\/science.aap9331","article-title":"Lacteal junction zippering protects against diet-induced obesity","volume":"361","author":"Zhang","year":"2018","journal-title":"Science"},{"key":"B101","doi-asserted-by":"publisher","first-page":"509","DOI":"10.3389\/fphys.2020.00509","article-title":"Lymphatic endothelial cell junctions: molecular regulation in physiology and diseases","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Physiol"},{"key":"B102","doi-asserted-by":"publisher","first-page":"6625","DOI":"10.1038\/ncomms7625","article-title":"EphB4 forward signalling regulates lymphatic valve development","volume":"6","author":"Zhang","year":"2015","journal-title":"Nat. Commun"},{"key":"B103","doi-asserted-by":"publisher","first-page":"421","DOI":"10.2176\/nmc.46.421","article-title":"Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage","volume":"46","author":"Zhao","year":"2006","journal-title":"Neurol. Med. Chir."},{"key":"B104","doi-asserted-by":"publisher","first-page":"1592","DOI":"10.1101\/gad.237677.114","article-title":"Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions","volume":"28","author":"Zheng","year":"2014","journal-title":"Genes Dev"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2020.627647\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,11]],"date-time":"2022-12-11T16:22:01Z","timestamp":1670775721000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2020.627647\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,14]]},"references-count":104,"alternative-id":["10.3389\/fcell.2020.627647"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2020.627647","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,14]]},"article-number":"627647"}}