{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:33:58Z","timestamp":1791516838985,"version":"4.3.4"},"reference-count":108,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T00:00:00Z","timestamp":1626739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1146800"],"award-info":[{"award-number":["1146800"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA\/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC\/VEGFD\/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease.<\/jats:p>","DOI":"10.3390\/ijms22147760","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T11:26:10Z","timestamp":1626780370000},"page":"7760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease: An Update"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5109-3222","authenticated-orcid":false,"given":"Genevieve A.","family":"Secker","sequence":"first","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha L.","family":"Harvey","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,20]]},"reference":[{"key":"ref_1","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_2","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_3","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1017\/S0025727300013053","article-title":"The white veins: Conceptual difficulties in the history of the lymphatics","volume":"12","author":"Lord","year":"1968","journal-title":"Med. Hist."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6500","DOI":"10.1126\/science.aax4063","article-title":"Biological functions of lymphatic vessels","volume":"369","author":"Petrova","year":"2020","journal-title":"Science"},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/nrd4608","article-title":"From sewer to saviour\u2014Targeting the lymphatic system to promote drug exposure and activity","volume":"14","author":"Trevaskis","year":"2015","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.addr.2020.10.002","article-title":"Lymph-directed immunotherapy\u2014Harnessing endogenous lymphatic distribution pathways for enhanced therapeutic outcomes in cancer","volume":"160","author":"Feeney","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_8","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":"Exp. Med."},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1007\/s00018-012-1110-6","article-title":"Flow control in our vessels: Vascular valves make sure there is no way back","volume":"70","author":"Bazigou","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"3305","DOI":"10.1016\/j.celrep.2019.05.050","article-title":"A Distinct Role of the Autonomic Nervous System in Modulating the Function of Lymphatic Vessels under Physiological and Tumor-Draining Conditions","volume":"27","author":"Bachmann","year":"2019","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4042","DOI":"10.1172\/JCI76509","article-title":"Intravital imaging of intestinal lacteals unveils lipid drainage through contractility","volume":"125","author":"Choe","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1172\/JCI71614","article-title":"Genetics of lymphatic anomalies","volume":"124","author":"Brouillard","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_15","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_16","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_17","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_18","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_19","first-page":"10","article-title":"A blood capillary plexus-derived population of progenitor cells contributes to genesis of the dermal lymphatic vasculature during embryonic development","volume":"145","author":"Betterman","year":"2018","journal-title":"Development"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Karkkainen, M.J., Haiko, P., Sainio, K., Partanen, J., Taipale, J., Petrova, T.V., Jeltsch, M., Jackson, D.G., Talikka, M., and Rauvala, H. (2004). Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat. Immunol., 74\u201380.","DOI":"10.1038\/ni1013"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/ng.321","article-title":"Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting","volume":"41","author":"Hogan","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1161\/CIRCRESAHA.111.250738","article-title":"CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo","volume":"109","author":"Bos","year":"2011","journal-title":"Circ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1172\/JCI83967","article-title":"Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD","volume":"126","author":"Bui","year":"2016","journal-title":"Clin. Invest."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s10456-015-9488-z","article-title":"ADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis","volume":"19","author":"Janssen","year":"2016","journal-title":"Angiogenesis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1161\/CIRCULATIONAHA.113.002779","article-title":"CCBE1 enhances lymphangiogenesis via a disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation","volume":"129","author":"Jeltsch","year":"2014","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1242\/dev.100495","article-title":"Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis","volume":"141","author":"Karpanen","year":"2014","journal-title":"Development"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1016\/j.celrep.2015.10.055","article-title":"Vegfc Regulates Bipotential Precursor Division and Prox1 Expression to Promote Lymphatic Identity in Zebrafish","volume":"13","author":"Koltowska","year":"2015","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1128\/MCB.25.6.2441-2449.2005","article-title":"Vascular endothelial growth factor D is dispensable for development of the lymphatic system","volume":"25","author":"Baldwin","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1038\/jid.2013.83","article-title":"Vascular endothelial growth factor-d modulates caliber and function of initial lymphatics in the dermis","volume":"133","author":"Levy","year":"2013","journal-title":"J. Investig. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1242\/dev.146969","article-title":"Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development","volume":"144","author":"Bower","year":"2017","journal-title":"Development"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/j.celrep.2019.07.055","article-title":"Evolutionary Differences in the Vegf\/Vegfr Code Reveal Organotypic Roles for the Endothelial Cell Receptor Kdr in Developmental Lymphangiogenesis","volume":"28","author":"Vogrin","year":"2019","journal-title":"Cell Rep."},{"key":"ref_32","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_33","doi-asserted-by":"crossref","first-page":"12677","DOI":"10.1073\/pnas.221449198","article-title":"A model for gene therapy of human hereditary lymphedema","volume":"98","author":"Karkkainen","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1038\/cr.2010.116","article-title":"VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis","volume":"20","author":"Zhang","year":"2010","journal-title":"Cell Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1038\/s41467-018-03692-0","article-title":"Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms","volume":"9","author":"Zhang","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1093\/emboj\/20.6.1223","article-title":"Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice","volume":"20","author":"Veikkola","year":"2001","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1242\/dev.151019","article-title":"Vascular endothelial growth factor signaling in development and disease","volume":"145","author":"Karaman","year":"2018","journal-title":"Development"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/84651","article-title":"Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3","volume":"7","author":"Makinen","year":"2001","journal-title":"Nat. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"708","DOI":"10.2353\/ajpath.2006.051200","article-title":"Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation","volume":"169","author":"Karpanen","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"3645","DOI":"10.1084\/jem.20170391","article-title":"Development and plasticity of meningeal lymphatic vessels","volume":"214","author":"Antila","year":"2017","journal-title":"Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1046\/j.1365-2613.1998.700404.x","article-title":"The vascular endothelial growth factor family; Proteins which guide the development of the vasculature","volume":"79","author":"Achen","year":"1998","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrm.2016.87","article-title":"Mechanisms and regulation of endothelial VEGF receptor signalling","volume":"17","author":"Simons","year":"2016","journal-title":"Nat. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1084\/jem.20021244","article-title":"Vascular permeability factor\/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis","volume":"196","author":"Nagy","year":"2002","journal-title":"Exp. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1084\/jem.20062642","article-title":"Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting","volume":"204","author":"Wirzenius","year":"2007","journal-title":"Exp. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1161\/01.RES.0000073584.46059.E3","article-title":"VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses","volume":"92","author":"Rissanen","year":"2003","journal-title":"Circ. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nature07083","article-title":"Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation","volume":"454","author":"Tammela","year":"2008","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"40973","DOI":"10.1074\/jbc.M304499200","article-title":"Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites","volume":"278","author":"Dixelius","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1038\/emboj.2010.30","article-title":"VEGF receptor 2\/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts","volume":"29","author":"Nilsson","year":"2010","journal-title":"EMBO J."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Kunnapuu, J., Bokharaie, H., and Jeltsch, M. (2021). Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs. Biology, 10.","DOI":"10.3390\/biology10020167"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2724","DOI":"10.1038\/s41467-020-16552-7","article-title":"Specific fibroblast subpopulations and neuronal structures provide local sources of Vegfc-processing components during zebrafish lymphangiogenesis","volume":"11","author":"Wang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1084\/jem.20030361","article-title":"Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D","volume":"198","author":"McColl","year":"2003","journal-title":"Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1182\/blood.2019001736","article-title":"Hemostasis stimulates lymphangiogenesis through release and activation of VEGFC","volume":"134","author":"Lim","year":"2019","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Jha, S.K., Rauniyar, K., Chronowska, E., Mattonet, K., Maina, E.W., Koistinen, H., Stenman, U.H., Alitalo, K., and Jeltsch, M. (2019). KLK3\/PSA and cathepsin D activate VEGF-C and VEGF-D. elife.","DOI":"10.7554\/eLife.44478.034"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1096\/fj.06-7060com","article-title":"Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2","volume":"21","author":"McColl","year":"2007","journal-title":"FASEB J."},{"key":"ref_56","first-page":"18","article-title":"Localised Collagen2a1 secretion supports lymphatic endothelial cell migration in the zebrafish embryo","volume":"147","author":"Chaudhury","year":"2020","journal-title":"Development"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12960","DOI":"10.1073\/pnas.1301415110","article-title":"Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation","volume":"110","author":"Leppanen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0925-4773(01)00518-4","article-title":"Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins","volume":"109","author":"Herzog","year":"2001","journal-title":"Mech. Dev."},{"key":"ref_59","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_60","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_61","doi-asserted-by":"crossref","first-page":"4797","DOI":"10.1242\/dev.129.20.4797","article-title":"Abnormal lymphatic vessel development in neuropilin 2 mutant mice","volume":"129","author":"Yuan","year":"2002","journal-title":"Development"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7442","DOI":"10.1038\/s41598-017-06637-7","article-title":"CD146 is required for VEGF-C-induced lymphatic sprouting during lymphangiogenesis","volume":"7","author":"Yan","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1161\/CIRCRESAHA.116.308504","article-title":"Functional Importance of a Proteoglycan Coreceptor in Pathologic Lymphangiogenesis","volume":"119","author":"Johns","year":"2016","journal-title":"Circ. Res."},{"key":"ref_64","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_65","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1002\/j.1460-2075.1996.tb00359.x","article-title":"A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases","volume":"15","author":"Joukov","year":"1996","journal-title":"EMBO J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1073\/pnas.95.2.548","article-title":"Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4)","volume":"95","author":"Achen","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4762","DOI":"10.1093\/emboj\/20.17.4762","article-title":"Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C\/D receptor VEGFR-3","volume":"20","author":"Makinen","year":"2001","journal-title":"EMBO J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3423","DOI":"10.1182\/blood-2005-04-1388","article-title":"Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways","volume":"106","author":"Salameh","year":"2005","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1161\/ATVBAHA.114.304881","article-title":"Molecular controls of lymphatic VEGFR3 signaling","volume":"35","author":"Deng","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1101\/gad.216226.113","article-title":"The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors","volume":"28","author":"Srinivasan","year":"2014","journal-title":"Genes Dev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1126\/sciadv.abe7359","article-title":"Mitochondrial respiration controls the Prox1-Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance","volume":"7","author":"Ma","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1242\/jcs.186767","article-title":"DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C","volume":"129","author":"Klein","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/nature08995","article-title":"Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis","volume":"465","author":"Sawamiphak","year":"2010","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nature09002","article-title":"Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis","volume":"465","author":"Wang","year":"2010","journal-title":"Nature"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3998","DOI":"10.1021\/bi061400n","article-title":"Vascular endothelial growth factor receptor-3 activity is modulated by its association with caveolin-1 on endothelial membrane","volume":"46","author":"Galvagni","year":"2007","journal-title":"Biochemistry"},{"key":"ref_76","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_77","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1161\/CIRCULATIONAHA.118.034961","article-title":"Vascular Endothelial Growth Factor Receptor 3 Regulates Endothelial Function Through beta-Arrestin 1","volume":"139","author":"Ma","year":"2019","journal-title":"Circulation"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"14","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":"ref_79","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.yexcr.2018.04.007","article-title":"VEGFR-3 signaling is regulated by a G-protein activator, activator of G-protein signaling 8, in lymphatic endothelial cells","volume":"368","author":"Sakima","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4424","DOI":"10.1172\/JCI64537","article-title":"Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling","volume":"122","author":"Pasula","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4025","DOI":"10.1172\/JCI96063","article-title":"Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes","volume":"128","author":"Wu","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s10456-021-09774-w","article-title":"The adaptor protein Grb2b is an essential modulator for lympho-venous sprout formation in the zebrafish trunk","volume":"24","author":"Mauri","year":"2021","journal-title":"Angiogenesis"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1172\/JCI63034","article-title":"Endothelial ERK signaling controls lymphatic fate specification","volume":"123","author":"Deng","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1101\/gad.565010","article-title":"Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development","volume":"24","author":"Saharinen","year":"2010","journal-title":"Genes Dev."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1172\/JCI85145","article-title":"Carbohydrate-binding protein CLEC14A regulates VEGFR-2- and VEGFR-3-dependent signals during angiogenesis and lymphangiogenesis","volume":"127","author":"Lee","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.2741\/3365","article-title":"The collagen receptor uPARAP\/Endo180","volume":"14","author":"Engelholm","year":"2009","journal-title":"Front. Biosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"5178","DOI":"10.1038\/s41467-018-07514-1","article-title":"uPARAP\/Endo180 receptor is a gatekeeper of VEGFR-2\/VEGFR-3 heterodimerisation during pathological lymphangiogenesis","volume":"9","author":"Durre","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","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":"ref_89","doi-asserted-by":"crossref","first-page":"684","DOI":"10.3389\/fphys.2020.00684","article-title":"The Importance of Mechanical Forces for in vitro Endothelial Cell Biology","volume":"11","author":"Gordon","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_90","first-page":"426","article-title":"A mechanosensory complex that mediates the endothelial cell response to fluid shear stress","volume":"437","author":"Tzima","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_91","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_92","doi-asserted-by":"crossref","unstructured":"Baeyens, N., Nicoli, S., Coon, B.G., Ross, T., Dries, K.V.D., 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.","DOI":"10.7554\/eLife.04645.017"},{"key":"ref_93","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_94","doi-asserted-by":"crossref","unstructured":"H\u00e4gerling, R., Hoppe, E., Dierkes, C., Stehling, M., Makinen, T., Butz, S., Vestweber, D., and Kiefer, F. (2018). Distinct roles of VE-cadherin for development and maintenance of specific lymph vessel beds. EMBO J.","DOI":"10.15252\/embj.201798271"},{"key":"ref_95","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_96","doi-asserted-by":"crossref","unstructured":"Cha, B., Ho, Y.-C., Geng, X., Mahamud, 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_97","first-page":"788","article-title":"Mechanoinduction of lymph vessel expansion","volume":"31","author":"Goedecke","year":"2011","journal-title":"EMBO J."},{"key":"ref_98","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. (2018). Identification of ILK as a critical regulator of VEGFR 3 signalling and lymphatic vascular growth. EMBO J., 38.","DOI":"10.15252\/embj.201899322"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41586-019-1912-x","article-title":"VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours","volume":"577","author":"Song","year":"2020","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/s41586-021-03489-0","article-title":"Meningeal lymphatics affect microglia responses and anti-Abeta immunotherapy","volume":"593","author":"Papadopoulos","year":"2021","journal-title":"Nature"},{"key":"ref_101","first-page":"62","article-title":"Cardiac lymphatics are heterogeneous in origin and respond to injury","volume":"522","author":"Klotz","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3402","DOI":"10.1172\/JCI97192","article-title":"The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction","volume":"128","author":"Vieira","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1161\/CIRCULATIONAHA.115.020143","article-title":"Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction","volume":"133","author":"Henri","year":"2016","journal-title":"Circulation"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41536-019-0079-2","article-title":"Vegfc\/d-dependent regulation of the lymphatic vasculature during cardiac regeneration is influenced by injury context","volume":"4","author":"Vivien","year":"2019","journal-title":"npj Regen. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-021-88064-3","article-title":"Isolation and characterisation of lymphatic endothelial cells from lung tissues affected by lymphangioleiomyomatosis","volume":"11","author":"Nishino","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Hominick, D., Silva, A., Khurana, N., Liu, Y., Dechow, P.C., Feng, J.Q., Pytowski, B., Rutkowski, J., Alitalo, K., and Dellinger, M.T. (2018). VEGF-C promotes the development of lymphatics in bone and bone loss. eLife, 7.","DOI":"10.7554\/eLife.34323"},{"key":"ref_107","first-page":"1","article-title":"Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation","volume":"11","author":"Zhang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Stacker, S.A., and Achen, M.G. (2018). Emerging Roles for VEGF-D in Human Disease. Biomolecules, 8.","DOI":"10.3390\/biom8010001"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7760\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:32:23Z","timestamp":1760164343000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7760"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,20]]},"references-count":108,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22147760"],"URL":"https:\/\/doi.org\/10.3390\/ijms22147760","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,20]]}}}