{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:29:50Z","timestamp":1790620190486,"version":"4.1.0"},"reference-count":227,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T00:00:00Z","timestamp":1618185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["NVKP_16-2016-1-0039"],"award-info":[{"award-number":["NVKP_16-2016-1-0039"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union and the Hungarian Government","award":["VEKOP-2.3.2-16-2016-00002"],"award-info":[{"award-number":["VEKOP-2.3.2-16-2016-00002"]}]},{"name":"Ministry for Innovation and Technology in Hungary","award":["Higher Education Institutional Excellence Program, within the framework of the Molecular Biology thematic program of the Semmelweis University"],"award-info":[{"award-number":["Higher Education Institutional Excellence Program, within the framework of the Molecular Biology thematic program of the Semmelweis University"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.<\/jats:p>","DOI":"10.3390\/ijms22083955","type":"journal-article","created":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T03:04:06Z","timestamp":1618196646000},"page":"3955","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3142-4071","authenticated-orcid":false,"given":"L\u00e1szl\u00f3","family":"B\u00e1lint","sequence":"first","affiliation":[{"name":"Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6304-2369","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Jakus","sequence":"additional","affiliation":[{"name":"Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","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":"ref_2","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1101\/gad.975002","article-title":"The rediscovery of the lymphatic system: Old and new insights into the development and biological function of the lymphatic vasculature","volume":"16","author":"Oliver","year":"2002","journal-title":"Genes Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/dvdy.20179","article-title":"Development of the lymphatic vascular system: A mystery unravels","volume":"231","author":"Hong","year":"2004","journal-title":"Dev. Dyn."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nri1258","article-title":"Lymphatic vasculature development","volume":"4","author":"Oliver","year":"2004","journal-title":"Nat. Rev. Immunol"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1038\/nature04480","article-title":"Lymphangiogenesis in development and human disease","volume":"438","author":"Alitalo","year":"2005","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","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":"ref_7","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1007\/s00418-008-0525-5","article-title":"Developmental and pathological lymphangiogenesis: From models to human disease","volume":"130","author":"Petrova","year":"2008","journal-title":"Histochem Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"a008268","DOI":"10.1101\/cshperspect.a008268","article-title":"Blood and lymphatic vessel formation","volume":"7","author":"Bautch","year":"2015","journal-title":"Cold Spring Harb. Perspect Biol."},{"key":"ref_9","doi-asserted-by":"crossref","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":"ref_10","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1093\/cvr\/cvw175","article-title":"Heterogeneity in the lymphatic vascular system and its origin","volume":"111","author":"Ulvmar","year":"2016","journal-title":"Cardiovasc Res."},{"key":"ref_11","first-page":"444","article-title":"Lymphatic Endothelial Cell Plasticity in Development and Disease","volume":"32","author":"Ma","year":"2017","journal-title":"Physiology (Bethesda)"},{"key":"ref_12","doi-asserted-by":"crossref","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":"ref_13","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1002\/aja.1001180308","article-title":"Fine structure of the lymphatic capillary and the adjoining connective tissue area","volume":"118","author":"Leak","year":"1966","journal-title":"Am. J. Anat"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1083\/jcb.36.1.129","article-title":"Ultrastructural studies on the lymphatic anchoring filaments","volume":"36","author":"Leak","year":"1968","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.cell.2010.01.045","article-title":"Lymphangiogenesis: Molecular mechanisms and future promise","volume":"140","author":"Tammela","year":"2010","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1172\/JCI71603","article-title":"Lymphangiogenic factors, mechanisms, and applications","volume":"124","author":"Zheng","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1242\/dev.089565","article-title":"Getting out and about: The emergence and morphogenesis of the vertebrate lymphatic vasculature","volume":"140","author":"Koltowska","year":"2013","journal-title":"Development"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1083\/jcb.201012094","article-title":"Lymphatic vascular morphogenesis in development, physiology, and disease","volume":"193","author":"Sabine","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1152\/physrev.1990.70.4.987","article-title":"Microlymphatics and lymph flow","volume":"70","year":"1990","journal-title":"Physiol Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.cell.2020.06.039","article-title":"The Lymphatic Vasculature in the 21(st) Century: Novel Functional Roles in Homeostasis and Disease","volume":"182","author":"Oliver","year":"2020","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/(SICI)1097-0185(199701)247:1<53::AID-AR8>3.0.CO;2-G","article-title":"The structure of superficial lymphatics in the human thigh: Precollectors","volume":"247","author":"Sacchi","year":"1997","journal-title":"Anat. Rec."},{"key":"ref_22","doi-asserted-by":"crossref","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":"ref_23","doi-asserted-by":"crossref","first-page":"R1524","DOI":"10.1152\/ajpregu.00888.2007","article-title":"Calcium sensitivity and cooperativity of permeabilized rat mesenteric lymphatics","volume":"294","author":"Dougherty","year":"2008","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.devcel.2009.06.017","article-title":"Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis","volume":"17","author":"Bazigou","year":"2009","journal-title":"Dev. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","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":"ref_26","doi-asserted-by":"crossref","first-page":"H48","DOI":"10.1152\/ajpheart.00133.2011","article-title":"Determinants of valve gating in collecting lymphatic vessels from rat mesentery","volume":"301","author":"Davis","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1196\/annals.1413.008","article-title":"Molecular regulation of lymphatic contractility","volume":"1131","author":"Muthuchamy","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_28","first-page":"177","article-title":"The fine structure and functioning of tissue channels and lymphatics","volume":"13","year":"1980","journal-title":"Lymphology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/cphy.c180015","article-title":"Lymphatic Vessel Network Structure and Physiology","volume":"9","author":"Breslin","year":"2018","journal-title":"Compr. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1146\/annurev-immunol-041015-055354","article-title":"The Lymphatic System: Integral Roles in Immunity","volume":"35","author":"Randolph","year":"2017","journal-title":"Annu. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.smim.2007.11.007","article-title":"Lymphatic drainage function and its immunological implications: From dendritic cell homing to vaccine design","volume":"20","author":"Swartz","year":"2008","journal-title":"Semin. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1101\/gad.1955910","article-title":"Current views on the function of the lymphatic vasculature in health and disease","volume":"24","author":"Wang","year":"2010","journal-title":"Genes Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1146\/annurev-med-051419-114417","article-title":"Lymphatic Vasculature: An Emerging Therapeutic Target and Drug Delivery Route","volume":"72","author":"Xu","year":"2021","journal-title":"Annu. Rev. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.addr.2020.12.005","article-title":"Development and aging of the lymphatic vascular system","volume":"169","author":"Petrova","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.semcancer.2009.05.005","article-title":"Tumor lymphatics","volume":"19","author":"Sleeman","year":"2009","journal-title":"Semin. Cancer Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.devcel.2018.03.021","article-title":"Emerging Concepts in Organ-Specific Lymphatic Vessels and Metabolic Regulation of Lymphatic Development","volume":"45","author":"Wong","year":"2018","journal-title":"Dev. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","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":"ref_38","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1161\/01.RES.76.4.536","article-title":"Nitric-Oxide Synthesis by Cultured Endothelial-Cells Is Modulated by Flow Conditions","volume":"76","author":"Noris","year":"1995","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1115\/1.1486468","article-title":"A new in vitro model to evaluate differential responses of endothelial cells to simulated arterial shear stress waveforms","volume":"124","author":"Blackman","year":"2002","journal-title":"J. Biomech Eng.-T Asme."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s10439-008-9452-9","article-title":"Gene expression of endothelial cells under pulsatile non-reversing vs. steady shear stress; comparison of nitric oxide production","volume":"36","author":"Yee","year":"2008","journal-title":"Ann. Biomed. Eng."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1161\/ATVBAHA.113.301826","article-title":"Endothelial Cell Sensing of Flow Direction","volume":"33","author":"Wang","year":"2013","journal-title":"Arter. Throm Vas."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Feaver, R.E., Gelfand, B.D., and Blackman, B.R. (2013). Human haemodynamic frequency harmonics regulate the inflammatory phenotype of vascular endothelial cells. Nat. Commun., 4.","DOI":"10.1038\/ncomms2530"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Uzarski, J.S., Scott, E.W., and McFetridge, P.S. (2013). Adaptation of endothelial cells to physiologically-modeled, variable shear stress. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057004"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Baeyens, N., Nicoli, S., Coon, B.G., Ross, T.D., Van den Dries, K., Han, J., Lauridsen, H.M., Mejean, C.O., Eichmann, A., and Thomas, J.L. (2015). Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point. eLife, 4.","DOI":"10.7554\/eLife.04645"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1080\/10739680600893909","article-title":"Lymph flow, shear stress, and lymphocyte velocity in rat mesenteric prenodal lymphatics","volume":"13","author":"Dixon","year":"2006","journal-title":"Microcirculation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"064016","DOI":"10.1117\/1.2135791","article-title":"Measuring microlymphatic flow using fast video microscopy","volume":"10","author":"Dixon","year":"2005","journal-title":"J. Biomed. Opt."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0007-1226(70)80066-2","article-title":"Lymphatic pressures and the flow of lymph","volume":"23","author":"Calnan","year":"1970","journal-title":"Br. J. Plast. Surg."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"S100","DOI":"10.1046\/j.1523-1755.1998.06720.x","article-title":"Shear stress and the endothelium","volume":"67","author":"Ballermann","year":"1998","journal-title":"Kidney Int. Suppl."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S1078-5884(97)80097-4","article-title":"In vivo wall shear stress measured by magnetic resonance velocity mapping in the normal human abdominal aorta","volume":"13","author":"Oyre","year":"1997","journal-title":"Eur. J. Vasc. Endovasc. Surg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"H2249","DOI":"10.1152\/ajpheart.00854.2003","article-title":"Reduced release of nitric oxide to shear stress in mesenteric arteries of aged rats","volume":"286","author":"Sun","year":"2004","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s10439-019-02350-w","article-title":"In Vivo MRI Assessment of Blood Flow in Arteries and Veins from Head-to-Toe Across Age and Sex in C57BL\/6 Mice","volume":"48","author":"Crouch","year":"2020","journal-title":"Ann. Biomed. Eng."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"586852","DOI":"10.3389\/fphys.2020.586852","article-title":"Remodeling of the Microvasculature: May the Blood Flow Be With You","volume":"11","author":"Santamaria","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nrm2596","article-title":"Mechanotransduction in vascular physiology and atherogenesis","volume":"10","author":"Hahn","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1161\/ATVBAHA.114.303422","article-title":"Shear stress-initiated signaling and its regulation of endothelial function","volume":"34","author":"Zhou","year":"2014","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1091\/mbc.E14-11-1522","article-title":"Biomechanics of vascular mechanosensation and remodeling","volume":"27","author":"Baeyens","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.bcp.2018.10.023","article-title":"Fluid shear stress sensing in vascular homeostasis and remodeling: Towards the development of innovative pharmacological approaches to treat vascular dysfunction","volume":"158","author":"Baeyens","year":"2018","journal-title":"Biochem. Pharm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"552","DOI":"10.3389\/fphys.2020.00552","article-title":"Blood Flow Forces in Shaping the Vascular System: A Focus on Endothelial Cell Behavior","volume":"11","author":"Campinho","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.gde.2019.08.002","article-title":"Mechanotransduction in cardiovascular morphogenesis and tissue engineering","volume":"57","author":"Duchemin","year":"2019","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1172\/JCI83083","article-title":"Endothelial fluid shear stress sensing in vascular health and disease","volume":"126","author":"Baeyens","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1089\/ars.2016.6685","article-title":"Endothelial Cell Responses to Biomechanical Forces in Lymphatic Vessels","volume":"25","author":"Sabine","year":"2016","journal-title":"Antioxid Redox Signal"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.mvr.2004.08.002","article-title":"Interstitial flow differentially stimulates blood and lymphatic endothelial cell morphogenesis in vitro","volume":"68","author":"Ng","year":"2004","journal-title":"Microvasc. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/bit.21185","article-title":"Engineered blood and lymphatic capillaries in 3-D VEGF-fibrin-collagen matrices with interstitial flow","volume":"96","author":"Helm","year":"2007","journal-title":"Biotechnol. Bioeng."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1126\/science.6681677","article-title":"Actin filament stress fibers in vascular endothelial cells in vivo","volume":"219","author":"Wong","year":"1983","journal-title":"Science"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/307648a0","article-title":"Induction of human vascular endothelial stress fibres by fluid shear stress","volume":"307","author":"Franke","year":"1984","journal-title":"Nature"},{"key":"ref_65","first-page":"639","article-title":"Fibronectin and F-actin redistribution in cultured endothelial cells exposed to shear stress","volume":"53","author":"Wechezak","year":"1985","journal-title":"Lab. Investig."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/jcp.1041390120","article-title":"Endothelial adherence under shear stress is dependent upon microfilament reorganization","volume":"139","author":"Wechezak","year":"1989","journal-title":"J. Cell Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1161\/01.RES.75.4.630","article-title":"Role of Ca2+ and protein kinase C in shear stress-induced actin depolymerization and endothelin 1 gene expression","volume":"75","author":"Morita","year":"1994","journal-title":"Circ. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1242\/jcs.109.4.713","article-title":"Mechanism of endothelial cell shape change and cytoskeletal remodeling in response to fluid shear stress","volume":"109","author":"Malek","year":"1996","journal-title":"J. Cell Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1172\/JCI117197","article-title":"Quantitative studies of endothelial cell adhesion. Directional remodeling of focal adhesion sites in response to flow forces","volume":"93","author":"Davies","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/jcp.1041630121","article-title":"Shear stress modulates endothelial cell morphology and F-actin organization through the regulation of focal adhesion-associated proteins","volume":"163","author":"Girard","year":"1995","journal-title":"J. Cell Physiol."},{"key":"ref_71","doi-asserted-by":"crossref","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":"ref_72","doi-asserted-by":"crossref","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. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"15779","DOI":"10.1073\/pnas.0503681102","article-title":"Synergy between interstitial flow and VEGF directs capillary morphogenesis in vitro through a gradient amplification mechanism","volume":"102","author":"Helm","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.biomaterials.2015.11.019","article-title":"Three-dimensional biomimetic model to reconstitute sprouting lymphangiogenesis in vitro","volume":"78","author":"Kim","year":"2016","journal-title":"Biomaterials"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1002\/aja.1000010310","article-title":"On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig","volume":"1","author":"Sabin","year":"1902","journal-title":"Am. J. Anat."},{"key":"ref_76","unstructured":"Kampmeier, O.F. (1969). Evolution and Comparative Morphology of the Lymphatic System, Thomas."},{"key":"ref_77","first-page":"245","article-title":"The early development of the lymphatic system in mouse embryos","volume":"13","year":"1975","journal-title":"Acta Morphol. Neerl Scand."},{"key":"ref_78","doi-asserted-by":"crossref","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":"ref_79","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1093\/emboj\/21.7.1505","article-title":"An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype","volume":"21","author":"Wigle","year":"2002","journal-title":"EMBO J."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4593","DOI":"10.1093\/emboj\/cdf470","article-title":"Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor","volume":"21","author":"Petrova","year":"2002","journal-title":"EMBO J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/dvdy.10163","article-title":"Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate","volume":"225","author":"Hong","year":"2002","journal-title":"Dev. Dyn."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1101\/gad.1588407","article-title":"Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature","volume":"21","author":"Srinivasan","year":"2007","journal-title":"Genes Dev."},{"key":"ref_83","doi-asserted-by":"crossref","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":"ref_84","doi-asserted-by":"crossref","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":"ref_85","doi-asserted-by":"crossref","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":"ref_86","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1126\/science.282.5390.946","article-title":"Cardiovascular failure in mouse embryos deficient in VEGF receptor-3","volume":"282","author":"Dumont","year":"1998","journal-title":"Science"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3793","DOI":"10.1182\/blood.V96.12.3793","article-title":"VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis","volume":"96","author":"Hamada","year":"2000","journal-title":"Blood"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3566","DOI":"10.1073\/pnas.92.8.3566","article-title":"Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development","volume":"92","author":"Kaipainen","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3546","DOI":"10.1093\/emboj\/cdg342","article-title":"T1alpha\/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema","volume":"22","author":"Schacht","year":"2003","journal-title":"EMBO J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.mod.2009.02.003","article-title":"NFATc1 regulates lymphatic endothelial development","volume":"126","author":"Kulkarni","year":"2009","journal-title":"Mech. Dev."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1038\/s41467-018-03959-6","article-title":"Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program","volume":"9","author":"Frye","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/aja.1000050107","article-title":"The development of the lymphatic system in rabbits","volume":"5","author":"Lewis","year":"1905","journal-title":"Am. J. Anat."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/aja.1000090104","article-title":"The lymphatic system in human embryos, with a consideration of the morphology of the system as a whole","volume":"9","author":"Sabin","year":"1909","journal-title":"Am. J. Anat."},{"key":"ref_94","first-page":"323","article-title":"The embryonic development of the main lymphatics in man","volume":"18","year":"1980","journal-title":"Acta Morphol. Neerl. Scand."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/nm1427","article-title":"Live imaging of lymphatic development in the zebrafish","volume":"12","author":"Yaniv","year":"2006","journal-title":"Nat. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S0002-9440(10)63851-5","article-title":"Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells","volume":"162","author":"Hirakawa","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/aja.1000100108","article-title":"The anatomy and development of the jugular lymph sacs in the domestic cat (Felis domestica)","volume":"10","author":"Huntington","year":"1910","journal-title":"Am. J. Anat."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/jemt.1159","article-title":"Development of the avian lymphatic system","volume":"55","author":"Wilting","year":"2001","journal-title":"Microsc. Res. Tech."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1089\/15396850360495673","article-title":"Lymphangioblasts in embryonic lymphangiogenesis","volume":"1","author":"Wilting","year":"2003","journal-title":"Lymphat Res. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ydbio.2005.12.043","article-title":"Dual origin of avian lymphatics","volume":"292","author":"Wilting","year":"2006","journal-title":"Dev. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1038\/nm1285","article-title":"A genetic Xenopus laevis tadpole model to study lymphangiogenesis","volume":"11","author":"Ny","year":"2005","journal-title":"Nat. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/(SICI)1097-0177(199912)216:4\/5<311::AID-DVDY1>3.0.CO;2-M","article-title":"Lymphangioblasts in the avian wing bud","volume":"216","author":"Schneider","year":"1999","journal-title":"Dev. Dyn."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1002\/dvdy.20737","article-title":"Mesenchymal cells with leukocyte and lymphendothelial characteristics in murine embryos","volume":"235","author":"Buttler","year":"2006","journal-title":"Dev. Dyn."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Buttler, K., Ezaki, T., and Wilting, J. (2008). Proliferating mesodermal cells in murine embryos exhibiting macrophage and lymphendothelial characteristics. BMC Dev. Biol., 8.","DOI":"10.1186\/1471-213X-8-43"},{"key":"ref_105","doi-asserted-by":"crossref","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":"ref_106","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1161\/CIRCRESAHA.116.306170","article-title":"Nonvenous origin of dermal lymphatic vasculature","volume":"116","author":"Ulvmar","year":"2015","journal-title":"Circ. Res."},{"key":"ref_107","doi-asserted-by":"crossref","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":"ref_108","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.ydbio.2019.05.002","article-title":"Isl1-expressing non-venous cell lineage contributes to cardiac lymphatic vessel development","volume":"452","author":"Maruyama","year":"2019","journal-title":"Dev. Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.devcel.2019.12.006","article-title":"A Second Heart Field-Derived Vasculogenic Niche Contributes to Cardiac Lymphatics","volume":"52","author":"Lioux","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_110","doi-asserted-by":"crossref","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":"ref_111","doi-asserted-by":"crossref","unstructured":"Gancz, D., Perlmoter, G., and Yaniv, K. (2020). Formation and Growth of Cardiac Lymphatics during Embryonic Development, Heart Regeneration, and Disease. Cold Spring Harb. Perspect. Biol., 12.","DOI":"10.1101\/cshperspect.a037176"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/emboj.2011.456","article-title":"Mechanoinduction of lymph vessel expansion","volume":"31","author":"Strilic","year":"2012","journal-title":"EMBO J."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Urner, S., Planas-Paz, L., Hilger, L.S., Henning, C., Branopolski, A., Kelly-Goss, M., Stanczuk, L., Pitter, B., Montanez, E., and Peirce, S.M. (2019). Identification of ILK as a critical regulator of VEGFR3 signalling and lymphatic vascular growth. EMBO J., 38.","DOI":"10.15252\/embj.201899322"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"H2176","DOI":"10.1152\/ajpheart.01011.2006","article-title":"Regulation of lymphatic capillary regeneration by interstitial flow in skin","volume":"292","author":"Goldman","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"H1402","DOI":"10.1152\/ajpheart.00038.2006","article-title":"Characterization of lymphangiogenesis in a model of adult skin regeneration","volume":"291","author":"Rutkowski","year":"2006","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1161\/01.RES.0000065621.69843.49","article-title":"Interstitial flow as a guide for lymphangiogenesis","volume":"92","author":"Boardman","year":"2003","journal-title":"Circ. Res."},{"key":"ref_117","doi-asserted-by":"crossref","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":"ref_118","first-page":"3590","article-title":"Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity","volume":"144","author":"Wang","year":"2017","journal-title":"Development"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"136","DOI":"10.3389\/fbioe.2020.00136","article-title":"Reduced Prenatal Pulmonary Lymphatic Function Is Observed in Clp1 (K\/K) Embryos With Impaired Motor Functions Including Fetal Breathing Movements in Preparation of the Developing Lung for Inflation at Birth","volume":"8","author":"Szoke","year":"2020","journal-title":"Front Bioeng. Biotechnol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3080","DOI":"10.1172\/JCI85794","article-title":"EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis","volume":"126","author":"Holdhus","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_121","doi-asserted-by":"crossref","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":"ref_122","doi-asserted-by":"crossref","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":"ref_123","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1182\/blood-2012-12-472142","article-title":"Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation","volume":"122","author":"Levet","year":"2013","journal-title":"Blood"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1101\/gad.282400.116","article-title":"Mechanotransduction activates canonical Wnt\/beta-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":"ref_125","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1172\/JCI89607","article-title":"RASA1 regulates the function of lymphatic vessel valves in mice","volume":"127","author":"Lapinski","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"ra97","DOI":"10.1126\/scisignal.2005413","article-title":"Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function","volume":"7","author":"Liu","year":"2014","journal-title":"Sci. Signal"},{"key":"ref_127","doi-asserted-by":"crossref","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":"ref_128","doi-asserted-by":"crossref","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":"Arter. Thromb. Vasc. Biol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"4441","DOI":"10.1242\/dev.140129","article-title":"Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development","volume":"143","author":"Wang","year":"2016","journal-title":"Development"},{"key":"ref_130","doi-asserted-by":"crossref","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":"ref_131","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1161\/CIRCRESAHA.112.269316","article-title":"Semaphorin3A, Neuropilin-1, and PlexinA1 are required for lymphatic valve formation","volume":"111","author":"Bouvree","year":"2012","journal-title":"Circ. Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1161\/CIRCRESAHA.112.269399","article-title":"An unexpected role of semaphorin3a-neuropilin-1 signaling in lymphatic vessel maturation and valve formation","volume":"111","author":"Jurisic","year":"2012","journal-title":"Circ Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1161\/CIRCRESAHA.118.313707","article-title":"YAP and TAZ Negatively Regulate Prox1 During Developmental and Pathologic Lymphangiogenesis","volume":"124","author":"Cho","year":"2019","journal-title":"Circ. Res."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Cha, B., Ho, Y.C., Geng, X., Mahamud, M.R., Chen, L., Kim, Y., Choi, D., Kim, T.H., Randolph, G.J., and Cao, X. (2020). YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling. Development, 147.","DOI":"10.1242\/dev.195453"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1182\/blood-2011-08-374363","article-title":"Loss-of-function germline GATA2 mutations in patients with MDS\/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature","volume":"119","author":"Kazenwadel","year":"2012","journal-title":"Blood"},{"key":"ref_136","doi-asserted-by":"crossref","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":"ref_137","doi-asserted-by":"crossref","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. Investig."},{"key":"ref_138","doi-asserted-by":"crossref","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. Investig."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1101\/gad.1727208","article-title":"Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity","volume":"22","author":"Johnson","year":"2008","journal-title":"Genes Dev."},{"key":"ref_140","doi-asserted-by":"crossref","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":"ref_141","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.ydbio.2015.10.022","article-title":"Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development","volume":"409","author":"Geng","year":"2016","journal-title":"Dev. Biol."},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Mahamud, M.R., Geng, X., Ho, Y.C., Cha, B., Kim, Y., Ma, J., Chen, L., Myers, G., Camper, S., and Mustacich, D. (2019). GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through miR-126. Development, 146.","DOI":"10.1101\/660068"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1182\/blood-2005-05-1994","article-title":"A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2","volume":"107","author":"Fuller","year":"2006","journal-title":"Blood"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1182\/blood-2010-02-270876","article-title":"Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling","volume":"116","author":"Bertozzi","year":"2010","journal-title":"Blood"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"25993","DOI":"10.1074\/jbc.M702327200","article-title":"Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells","volume":"282","author":"Kato","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/j.1538-7836.2009.03372.x","article-title":"Novel interactions in platelet biology: CLEC-2\/podoplanin and laminin\/GPVI","volume":"7","author":"Ozaki","year":"2009","journal-title":"J. Thromb. Haemost."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1182\/blood-2009-04-216069","article-title":"Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation","volume":"115","author":"Uhrin","year":"2010","journal-title":"Blood"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/378298a0","article-title":"Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk","volume":"378","author":"Turner","year":"1995","journal-title":"Nature"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/378303a0","article-title":"Syk tyrosine kinase required for mouse viability and B-cell development","volume":"378","author":"Cheng","year":"1995","journal-title":"Nature"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1074-7613(00)00005-4","article-title":"Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors","volume":"13","author":"Wang","year":"2000","journal-title":"Immunity"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1126\/science.1079477","article-title":"Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk","volume":"299","author":"Abtahian","year":"2003","journal-title":"Science"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.devcel.2006.07.007","article-title":"Syk and Slp-76 mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development","volume":"11","author":"Sebzda","year":"2006","journal-title":"Dev. Cell"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"3725","DOI":"10.1172\/JCI36077","article-title":"Endothelial cell O-glycan deficiency causes blood\/lymphatic misconnections and consequent fatty liver disease in mice","volume":"118","author":"Fu","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1242\/dev.025353","article-title":"Phospholipase Cgamma2 is necessary for separation of blood and lymphatic vasculature in mice","volume":"136","author":"Ichise","year":"2009","journal-title":"Development"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"24494","DOI":"10.1074\/jbc.M110.130575","article-title":"Essential in vivo roles of the C-type lectin receptor CLEC-2: Embryonic\/neonatal lethality of CLEC-2-deficient mice by blood\/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets","volume":"285","author":"Inoue","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1172\/JCI70422","article-title":"Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life","volume":"124","author":"Hess","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1161\/ATVBAHA.116.308020","article-title":"Postnatal Deletion of Podoplanin in Lymphatic Endothelium Results in Blood Filling of the Lymphatic System and Impairs Dendritic Cell Migration to Lymph Nodes","volume":"37","author":"Bianchi","year":"2017","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1182\/blood-2016-04-636415","article-title":"Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation","volume":"128","author":"Welsh","year":"2016","journal-title":"Blood"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1172\/JCI57513","article-title":"Blood flow reprograms lymphatic vessels to blood vessels","volume":"122","author":"Chen","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1172\/JCI79386","article-title":"Lymph flow regulates collecting lymphatic vessel maturation in vivo","volume":"125","author":"Sweet","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.1172\/JCI125044","article-title":"Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage","volume":"129","author":"Reed","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.3389\/fimmu.2019.03043","article-title":"Lymph Flow Induces the Postnatal Formation of Mature and Functional Meningeal Lymphatic Vessels","volume":"10","author":"Balint","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.celrep.2018.09.049","article-title":"Complementary Wnt Sources Regulate Lymphatic Vascular Development via PROX1-Dependent Wnt\/beta-Catenin Signaling","volume":"25","author":"Cha","year":"2018","journal-title":"Cell Rep."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3233\/BIR-1985-22201","article-title":"Particle flow behavior in models of branching vessels. II. Effects of branching angle and diameter ratio on flow patterns","volume":"22","author":"Karino","year":"1985","journal-title":"Biorheology"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/j.1749-6632.1987.tb33063.x","article-title":"Flow patterns in vessels of simple and complex geometries","volume":"516","author":"Karino","year":"1987","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"17308","DOI":"10.1073\/pnas.1413725111","article-title":"Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling","volume":"111","author":"Baeyens","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"12817","DOI":"10.1073\/pnas.1817070115","article-title":"Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation","volume":"115","author":"Nonomura","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_168","doi-asserted-by":"crossref","unstructured":"Choi, D., Park, E., Jung, E., Cha, B., Lee, S., Yu, J., Kim, P.M., Lee, S., Hong, Y.J., and Koh, C.J. (2019). Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance. JCI Insight, 4.","DOI":"10.1172\/jci.insight.125068"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"8329","DOI":"10.1038\/ncomms9329","article-title":"Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia","volume":"6","author":"Lukacs","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_170","doi-asserted-by":"crossref","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":"ref_171","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1126\/science.1193270","article-title":"Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels","volume":"330","author":"Coste","year":"2010","journal-title":"Science"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/nature10812","article-title":"Piezo proteins are pore-forming subunits of mechanically activated channels","volume":"483","author":"Coste","year":"2012","journal-title":"Nature"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/nature15247","article-title":"Architecture of the mammalian mechanosensitive Piezo1 channel","volume":"527","author":"Ge","year":"2015","journal-title":"Nature"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"282","DOI":"10.4161\/chan.21064","article-title":"Gating the mechanical channel Piezo1: A comparison between whole-cell and patch recording","volume":"6","author":"Gottlieb","year":"2012","journal-title":"Channels (Austin)"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"C1411","DOI":"10.1152\/ajpcell.1992.262.6.C1411","article-title":"Flow-induced calcium transients in single endothelial cells: Spatial and temporal analysis","volume":"262","author":"Geiger","year":"1992","journal-title":"Am. J. Physiol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1007\/BF00374230","article-title":"Shear stress induced membrane currents and calcium transients in human vascular endothelial cells","volume":"421","author":"Schwarz","year":"1992","journal-title":"Pflugers Arch."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/nature13701","article-title":"Piezo1 integration of vascular architecture with physiological force","volume":"515","author":"Li","year":"2014","journal-title":"Nature"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"10347","DOI":"10.1073\/pnas.1409233111","article-title":"Piezo1, a mechanically activated ion channel, is required for vascular development in mice","volume":"111","author":"Ranade","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/bs.ctm.2016.11.001","article-title":"Piezo1 Channels in Vascular Development and the Sensing of Shear Stress","volume":"79","author":"Hyman","year":"2017","journal-title":"Curr. Top Membr."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1172\/JCI87442","article-title":"Laminar flow downregulates Notch activity to promote lymphatic sprouting","volume":"127","author":"Choi","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1161\/CIRCRESAHA.116.309548","article-title":"ORAI1 Activates Proliferation of Lymphatic Endothelial Cells in Response to Laminar Flow Through Kruppel-Like Factors 2 and 4","volume":"120","author":"Choi","year":"2017","journal-title":"Circ. Res."},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Geng, X., Yanagida, K., Akwii, R.G., Choi, D., Chen, L., Ho, Y., Cha, B., Mahamud, M.R., Berman de Ruiz, K., and Ichise, H. (2020). S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress-dependent VEGF-C signaling. JCI Insight, 5.","DOI":"10.1172\/jci.insight.137652"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"H1283","DOI":"10.1152\/ajpheart.00544.2019","article-title":"Ca(2+) release-activated Ca(2+) channels are responsible for histamine-induced Ca(2+) entry, permeability increase, and interleukin synthesis in lymphatic endothelial cells","volume":"318","author":"Si","year":"2020","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_184","doi-asserted-by":"crossref","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":"ref_185","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/nature03952","article-title":"A mechanosensory complex that mediates the endothelial cell response to fluid shear stress","volume":"437","author":"Tzima","year":"2005","journal-title":"Nature"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.1242\/jcs.02541","article-title":"Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells","volume":"118","author":"Fleming","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1161\/ATVBAHA.109.186692","article-title":"PECAM-1 is necessary for flow-induced vascular remodeling","volume":"29","author":"Chen","year":"2009","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1016\/j.cub.2012.08.051","article-title":"Localized tensional forces on PECAM-1 elicit a global mechanotransduction response via the integrin-RhoA pathway","volume":"22","author":"Collins","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.cub.2013.04.049","article-title":"Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1","volume":"23","author":"Conway","year":"2013","journal-title":"Curr. Biol."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"335","DOI":"10.4161\/19336918.2014.968498","article-title":"Mechanotransduction of shear stress occurs through changes in VE-cadherin and PECAM-1 tension: Implications for cell migration","volume":"9","author":"Conway","year":"2015","journal-title":"Cell Adh. Migr."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1161\/CIRCRESAHA.110.229955","article-title":"Role of PECAM-1 in arteriogenesis and specification of preexisting collaterals","volume":"107","author":"Chen","year":"2010","journal-title":"Circ. Res."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1161\/01.ATV.0000170136.71970.5f","article-title":"PECAM-1 mediates NO-dependent dilation of arterioles to high temporal gradients of shear stress","volume":"25","author":"Bagi","year":"2005","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1159\/000083094","article-title":"Effects of flow patterns on the localization and expression of VE-cadherin at vascular endothelial cell junctions: In vivo and in vitro investigations","volume":"42","author":"Miao","year":"2005","journal-title":"J. Vasc. Res."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"599281","DOI":"10.3389\/fcell.2020.599281","article-title":"Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role","volume":"8","author":"Wang","year":"2020","journal-title":"Front Cell Dev. Biol."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/21224","article-title":"Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation","volume":"399","author":"Dimmeler","year":"1999","journal-title":"Nature"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/21218","article-title":"Regulation of endothelium-derived nitric oxide production by the protein kinase Akt","volume":"399","author":"Fulton","year":"1999","journal-title":"Nature"},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"H1819","DOI":"10.1152\/ajpheart.00214.2002","article-title":"Shear stress stimulates phosphorylation of eNOS at Ser(635) by a protein kinase A-dependent mechanism","volume":"283","author":"Boo","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1161\/01.RES.0000089257.94002.96","article-title":"Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase","volume":"93","author":"Jin","year":"2003","journal-title":"Circ. Res."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/jcp.21024","article-title":"Effects of different types of fluid shear stress on endothelial cell proliferation and survival","volume":"212","author":"Kadohama","year":"2007","journal-title":"J. Cell Physiol."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"3988","DOI":"10.1182\/blood-2012-12-474601","article-title":"Endothelial RAF1\/ERK activation regulates arterial morphogenesis","volume":"121","author":"Deng","year":"2013","journal-title":"Blood"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"4826","DOI":"10.1038\/s41467-018-07172-3","article-title":"Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility","volume":"9","author":"Casado","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1084\/jem.20020587","article-title":"Lymphangiogenic gene therapy with minimal blood vascular side effects","volume":"196","author":"Saaristo","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_203","doi-asserted-by":"crossref","unstructured":"Dellinger, M.T., Meadows, S.M., Wynne, K., Cleaver, O., and Brekken, R.A. (2013). Vascular endothelial growth factor receptor-2 promotes the development of the lymphatic vasculature. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074686"},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1096\/fj.06-6656com","article-title":"Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis","volume":"21","author":"Goldman","year":"2007","journal-title":"FASEB J."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/ncb3320","article-title":"Blood flow drives lumen formation by inverse membrane blebbing during angiogenesis in vivo","volume":"18","author":"Gebala","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1242\/dev.02883","article-title":"Vascular remodeling of the mouse yolk sac requires hemodynamic force","volume":"134","author":"Lucitti","year":"2007","journal-title":"Development"},{"key":"ref_207","doi-asserted-by":"crossref","unstructured":"Franco, C.A., Jones, M.L., Bernabeu, M.O., Geudens, I., Mathivet, T., Rosa, A., Lopes, F.M., Lima, A.P., Ragab, A., and Collins, R.T. (2015). Dynamic endothelial cell rearrangements drive developmental vessel regression. PLoS Biol., 13.","DOI":"10.1371\/journal.pbio.1002163"},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1161\/01.ATV.17.10.2245","article-title":"Increased blood flow induces regression of intimal hyperplasia","volume":"17","author":"Mattsson","year":"1997","journal-title":"Arter. Thromb Vasc. Biol."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1242\/dev.00929","article-title":"Flow regulates arterial-venous differentiation in the chick embryo yolk sac","volume":"131","author":"Moyon","year":"2004","journal-title":"Development"},{"key":"ref_210","doi-asserted-by":"crossref","unstructured":"Kizhatil, K., Ryan, M., Marchant, J.K., Henrich, S., and John, S.W. (2014). Schlemm\u2019s canal is a unique vessel with a combination of blood vascular and lymphatic phenotypes that forms by a novel developmental process. PLoS Biol., 12.","DOI":"10.1371\/journal.pbio.1001912"},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"3975","DOI":"10.1172\/JCI75395","article-title":"The Schlemm\u2019s canal is a VEGF-C\/VEGFR-3-responsive lymphatic-like vessel","volume":"124","author":"Aspelund","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"3960","DOI":"10.1172\/JCI75392","article-title":"Lymphatic regulator PROX1 determines Schlemm\u2019s canal integrity and identity","volume":"124","author":"Park","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1681\/ASN.2017090962","article-title":"Ascending Vasa Recta Are Angiopoietin\/Tie2-Dependent Lymphatic-Like Vessels","volume":"29","author":"Scott","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_214","doi-asserted-by":"crossref","unstructured":"Pawlak, J.B., Balint, L., Lim, L., Ma, W., Davis, R.B., Benyo, Z., Soares, M.J., Oliver, G., Kahn, M.L., and Jakus, Z. (2019). Lymphatic mimicry in maternal endothelial cells promotes placental spiral artery remodeling. J. Clin. Investig.","DOI":"10.1172\/JCI120446"},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nature03511","article-title":"Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity","volume":"435","author":"You","year":"2005","journal-title":"Nature"},{"key":"ref_216","doi-asserted-by":"crossref","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":"ref_217","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.3892\/ijmm.2017.3108","article-title":"Fluid shear stress regulates vascular remodeling via VEGFR-3 activation, although independently of its ligand, VEGF-C, in the uterus during pregnancy","volume":"40","author":"Park","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1038\/ng.913","article-title":"Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia","volume":"43","author":"Hahn","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1038\/ng.923","article-title":"Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome)","volume":"43","author":"Ostergaard","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_220","doi-asserted-by":"crossref","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":"ref_221","doi-asserted-by":"crossref","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":"ref_222","doi-asserted-by":"crossref","first-page":"E1002","DOI":"10.1002\/humu.21127","article-title":"Novel missense mutations in the FOXC2 gene alter transcriptional activity","volume":"30","author":"Damstra","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1007\/s00439-014-1456-y","article-title":"Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome","volume":"133","author":"Alders","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/pd.2130","article-title":"A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: Possible correlation with poor response to fetal therapy","volume":"28","author":"Ma","year":"2008","journal-title":"Prenat. Diagn."},{"key":"ref_225","doi-asserted-by":"crossref","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":"ref_226","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1093\/hmg\/7.13.2073","article-title":"Hereditary lymphedema: Evidence for linkage and genetic heterogeneity","volume":"7","author":"Ferrell","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1002\/ajmg.a.31703","article-title":"A novel VEGFR3 mutation causes Milroy disease","volume":"143A","author":"Butler","year":"2007","journal-title":"Am. J. Med. Genet A"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/3955\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:38:33Z","timestamp":1760366313000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/3955"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,12]]},"references-count":227,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22083955"],"URL":"https:\/\/doi.org\/10.3390\/ijms22083955","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,12]]}}}