{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:56:21Z","timestamp":1792788981368,"version":"4.5.0"},"reference-count":154,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T00:00:00Z","timestamp":1614038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004212","name":"P\u00e4ivikki and Sakari Sohlberg Foundation","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/501100004212","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["337430"],"award-info":[{"award-number":["337430"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007417","name":"Paulon S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/501100007417","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Einar and Karin Stroem Foundation","award":["-"],"award-info":[{"award-number":["-"]}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["21036"],"award-info":[{"award-number":["21036"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011842","name":"Opetushallitus","doi-asserted-by":"publisher","award":["TM-20-11320"],"award-info":[{"award-number":["TM-20-11320"]}],"id":[{"id":"10.13039\/501100011842","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymph\u00adangiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal propeptides before they can activate their receptors. At least five different proteases mediate the activating cleavage of VEGF-C: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, and thrombin. All of these proteases except for ADAMTS3 can also activate VEGF-D. Processing by different proteases results in distinct forms of the \u201cmature\u201d growth factors, which differ in affinity and receptor activation potential. The \u201cdefault\u201d VEGF-C-activating enzyme ADAMTS3 does not activate VEGF-D, and therefore, VEGF-C and VEGF-D do function in different contexts. VEGF-C itself is also regulated in different contexts by distinct proteases. During embryonic development, ADAMTS3 activates VEGF-C. The other activating proteases are likely important for non-developmental lymphangiogenesis during, e.g., tissue regeneration, inflammation, immune response, and pathological tumor-associated lymphangiogenesis. The better we understand these events at the molecular level, the greater our chances of developing successful therapies targeting VEGF-C and VEGF-D for diseases involving the lymphatics such as lymphedema or cancer.<\/jats:p>","DOI":"10.3390\/biology10020167","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T12:40:16Z","timestamp":1614084016000},"page":"167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9509-1862","authenticated-orcid":false,"given":"Jaana","family":"K\u00fcnnapuu","sequence":"first","affiliation":[{"name":"Drug Research Program, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3826-7582","authenticated-orcid":false,"given":"Honey","family":"Bokharaie","sequence":"additional","affiliation":[{"name":"Drug Research Program, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2890-7790","authenticated-orcid":false,"given":"Michael","family":"Jeltsch","sequence":"additional","affiliation":[{"name":"Drug Research Program, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland"},{"name":"Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland"},{"name":"Wihuri Research Institute, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"de Groof, A., Guelen, L., Deijs, M., van der Wal, Y., Miyata, M., Ng, K.S., van Grinsven, L., Simmelink, B., Biermann, Y., and Grisez, L. (2015). A Novel Virus Causes Scale Drop Disease in Lates Calcarifer. PLOS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005074"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1128\/jvi.68.1.84-92.1994","article-title":"Homologs of Vascular Endothelial Growth Factor Are Encoded by the Poxvirus Orf Virus","volume":"68","author":"Lyttle","year":"1994","journal-title":"J. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1093\/emboj\/18.2.363","article-title":"A Novel Vascular Endothelial Growth Factor Encoded by Orf Virus, VEGF-E, Mediates Angiogenesis via Signalling through VEGFR-2 (KDR) but Not VEGFR-1 (Flt-1) Receptor Tyrosine Kinases","volume":"18","author":"Meyer","year":"1999","journal-title":"EMBO J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"31273","DOI":"10.1074\/jbc.273.47.31273","article-title":"A Novel Type of Vascular Endothelial Growth Factor, VEGF-E (NZ-7 VEGF), Preferentially Utilizes KDR\/Flk-1 Receptor and Carries a Potent Mitotic Activity without Heparin-Binding Domain","volume":"273","author":"Ogawa","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9885","DOI":"10.1074\/jbc.M809071200","article-title":"Snake Venom Vascular Endothelial Growth Factors (VEGF-Fs) Exclusively Vary Their Structures and Functions among Species","volume":"284","author":"Yamazaki","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/S0092-8674(00)80456-0","article-title":"Crystal Structure at 1.7 \u00c5 Resolution of VEGF in Complex with Domain 2 of the Flt-1 Receptor","volume":"91","author":"Wiesmann","year":"1997","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"11197","DOI":"10.1074\/jbc.273.18.11197","article-title":"Requirements for Binding and Signaling of the Kinase Domain Receptor for Vascular Endothelial Growth Factor","volume":"273","author":"Fuh","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1073\/pnas.0914318107","article-title":"Structural Determinants of Growth Factor Binding and Specificity by VEGF Receptor 2","volume":"107","author":"Prota","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","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":"Tvorogov","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.cell.2019.01.021","article-title":"VEGF in Signaling and Disease: Beyond Discovery and Development","volume":"176","author":"Apte","year":"2019","journal-title":"Cell"},{"key":"ref_11","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. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/380435a0","article-title":"Abnormal Blood Vessel Development and Lethality in Embryos Lacking a Single VEGF Allele","volume":"380","author":"Carmeliet","year":"1996","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/380439a0","article-title":"Heterozygous Embryonic Lethality Induced by Targeted Inactivation of the VEGF Gene","volume":"380","author":"Ferrara","year":"1996","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/ni1013","article-title":"Vascular Endothelial Growth Factor C Is Required for Sprouting of the First Lymphatic Vessels from Embryonic Veins","volume":"5","author":"Karkkainen","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Rodamilans, B., Shan, H., Pasin, F., and Garc\u00eda, J.A. (2018). Plant Viral Proteases: Beyond the Role of Peptide Cutters. Front. Plant Sci., 9.","DOI":"10.3389\/fpls.2018.00666"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1111\/nph.15156","article-title":"Unravelling the Mode of Action of Plant Proteases","volume":"218","author":"Rivas","year":"2018","journal-title":"New Phytol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8501","DOI":"10.1073\/pnas.0809885106","article-title":"The Drosophila DPP Signal Is Produced by Cleavage of Its Proprotein at Evolutionary Diversified Furin-Recognition Sites","volume":"106","author":"Shimmi","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1038\/emboj.2012.42","article-title":"Protease Signalling: The Cutting Edge","volume":"31","author":"Turk","year":"2012","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2013.11.002","article-title":"Extracellular Regulation of VEGF: Isoforms, Proteolysis, and Vascular Patterning","volume":"25","author":"Vempati","year":"2014","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/s41598-017-00100-3","article-title":"RNA-Sequencing Data Supports the Existence of Novel VEGFA Splicing Events but Not of VEGFA Xxx b Isoforms","volume":"7","author":"Bridgett","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7788","DOI":"10.1074\/jbc.271.13.7788","article-title":"The Carboxyl-Terminal Domain(111165) of Vascular Endothelial Growth Factor Is Critical for Its Mitogenic Potency","volume":"271","author":"Keyt","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1091\/mbc.4.12.1317","article-title":"The Vascular Endothelial Growth Factor (VEGF) Isoforms: Differential Deposition into the Subepithelial Extracellular Matrix and Bioactivity of Extracellular Matrix-Bound VEGF","volume":"4","author":"Park","year":"1993","journal-title":"Mol. Biol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/8379","article-title":"Impaired Myocardial Angiogenesis and Ischemic Cardiomyopathy in Mice Lacking the Vascular Endothelial Growth Factor Isoforms VEGF 164 and VEGF 188","volume":"5","author":"Carmeliet","year":"1999","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2684","DOI":"10.1101\/gad.242002","article-title":"Spatially Restricted Patterning Cues Provided by Heparin-Binding VEGF-A Control Blood Vessel Branching Morphogenesis","volume":"16","author":"Ruhrberg","year":"2002","journal-title":"Genes Dev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1083\/jcb.200302047","article-title":"VEGF Guides Angiogenic Sprouting Utilizing Endothelial Tip Cell Filopodia","volume":"161","author":"Gerhardt","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13390","DOI":"10.1074\/jbc.272.20.13390","article-title":"Extracellular Cleavage of the Vascular Endothelial Growth Factor 189-Amino Acid Form by Urokinase Is Required for Its Mitogenic Effect","volume":"272","author":"Moro","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"26031","DOI":"10.1016\/S0021-9258(18)35712-0","article-title":"Dual Regulation of Vascular Endothelial Growth Factor Bioavailability by Genetic and Proteolytic Mechanisms","volume":"267","author":"Houck","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1091\/mbc.e09-07-0590","article-title":"Binding to the Extracellular Matrix and Proteolytic Processing: Two Key Mechanisms Regulating Vascular Endothelial Growth Factor Action","volume":"21","author":"Ferrara","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Uslu, \u00d6., Herold, J., and Kanse, S.M. (2019). VEGF-A-Cleavage by FSAP and Inhibition of Neo-Vascularization. Cells, 8.","DOI":"10.3390\/cells8111396"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1083\/jcb.200409115","article-title":"Processing of VEGF-A by Matrix Metalloproteinases Regulates Bioavailability and Vascular Patterning in Tumors","volume":"169","author":"Lee","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/sj.jidsymp.5650016","article-title":"Molecular Mechanisms of VEGF-A Action during Tissue Repair","volume":"11","author":"Eming","year":"2006","journal-title":"J. Investig. Dermatol. Symp. Proc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"17976","DOI":"10.1074\/jbc.M113.451831","article-title":"Proteolytic Processing Regulates Placental Growth Factor Activities","volume":"288","author":"Hoffmann","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"21217","DOI":"10.1074\/jbc.274.30.21217","article-title":"Differential Binding of Vascular Endothelial Growth Factor B Splice and Proteolytic Isoforms to Neuropilin-1","volume":"274","author":"Makinen","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19310","DOI":"10.1074\/jbc.271.32.19310","article-title":"Genomic Organization of the Mouse and Human Genes for Vascular Endothelial Growth Factor B (VEGF-B) and Characterization of a Second Splice Isoform","volume":"271","author":"Olofsson","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"D624","DOI":"10.1093\/nar\/gkx1134","article-title":"The MEROPS Database of Proteolytic Enzymes, Their Substrates and Inhibitors in 2017 and a Comparison with Peptidases in the PANTHER Database","volume":"46","author":"Rawlings","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s11030-006-9027-3","article-title":"Molecular and Functional Diversity of Vascular Endothelial Growth Factors","volume":"10","author":"Yamazaki","year":"2006","journal-title":"Mol. Divers."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1006\/bbrc.2000.4145","article-title":"A Functional Prothrombin Gene Product Is Synthesized by Human Kidney Cells","volume":"280","author":"Stenberg","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3898","DOI":"10.1093\/emboj\/16.13.3898","article-title":"Proteolytic Processing Regulates Receptor Specificity and Activity of VEGF-C","volume":"16","author":"Joukov","year":"1997","journal-title":"EMBO J."},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1172\/JCI200317220","article-title":"The Secretory Proprotein Convertases Furin, PC5, and PC7 Activate VEGF-C to Induce Tumorigenesis","volume":"111","author":"Siegfried","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_41","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":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Janssen, L., Dupont, L., Bekhouche, M., Noel, A., Leduc, C., Voz, M., Peers, B., Cataldo, D., Apte, S.S., and Dubail, J. (2015). ADAMTS3 Activity Is Mandatory for Embryonic Lymphangiogenesis and Regulates Placental Angiogenesis. Angiogenesis, 1\u201313.","DOI":"10.1007\/s10456-015-9488-z"},{"key":"ref_43","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\u2013Mediated Vascular Endothelial Growth Factor-C Activation","volume":"129","author":"Jeltsch","year":"2014","journal-title":"Circulation"},{"key":"ref_44","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":"J. Exp. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e44478","DOI":"10.7554\/eLife.44478","article-title":"KLK3\/PSA and Cathepsin D Activate VEGF-C and VEGF-D","volume":"8","author":"Jha","year":"2019","journal-title":"eLife"},{"key":"ref_46","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_47","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1096\/fj.05-5646com","article-title":"Functional Interaction of VEGF-C and VEGF-D with Neuropilin Receptors","volume":"20","author":"Heckman","year":"2006","journal-title":"FASEB J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1055\/s-0037-1615158","article-title":"Peripheral Blood Platelets Express VEGF-C and VEGF Which Are Released during Platelet Activation","volume":"80","author":"Wartiovaara","year":"1998","journal-title":"Thromb. Haemost."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1089\/lrb.2015.0060","article-title":"Applications of Platelet-Rich Plasma in Lymphedema","volume":"14","author":"Cirak","year":"2016","journal-title":"Lymphat. Res. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"483","DOI":"10.2337\/diacare.24.3.483","article-title":"Effectiveness of Platelet Releasate for the Treatment of Diabetic Neuropathic Foot Ulcers","volume":"24","author":"Margolis","year":"2001","journal-title":"Diabetes Care"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3461","DOI":"10.1074\/mcp.M116.059154","article-title":"Comprehensive Proteome Profiling of Platelet Identified a Protein Profile Predictive of Responses to An Antiplatelet Agent Sarpogrelate","volume":"15","author":"Lee","year":"2016","journal-title":"Mol. Cell. Proteom."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e00573","DOI":"10.1002\/prp2.573","article-title":"Complex Formation of Anti-VEGF-C with VEGF-C Released during Blood Coagulation Resulted in an Artifact in Its Serum Pharmacokinetics","volume":"8","author":"Yadav","year":"2020","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_53","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_54","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1073\/pnas.93.5.1988","article-title":"Vascular Endothelial Growth Factor-Related Protein: A Ligand and Specific Activator of the Tyrosine Kinase Receptor Flt4","volume":"93","author":"Lee","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1101\/gad.9.7.794","article-title":"Plasminogen Deficiency Causes Severe Thrombosis but Is Compatible with Development and Reproduction","volume":"9","author":"Bugge","year":"1995","journal-title":"Genes Dev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/BF00210737","article-title":"Plasminogen with Type-I Mutation Is Polymorphic in the Japanese Population","volume":"90","author":"Kikuchi","year":"1992","journal-title":"Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1038\/ng.484","article-title":"Mutations in CCBE1 Cause Generalized Lymph Vessel Dysplasia in Humans","volume":"41","author":"Alders","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/ajmg.1320340429","article-title":"Autosomal Recessive Intestinal Lymphangiectasia and Lymphedema, with Facial Anomalies and Mental Retardation","volume":"34","author":"Hennekam","year":"1989","journal-title":"Am. J. Med. Genet."},{"key":"ref_59","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_60","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_61","doi-asserted-by":"crossref","first-page":"31502","DOI":"10.1074\/jbc.M103466200","article-title":"Procollagen II Amino Propeptide Processing by ADAMTS-3 INSIGHTS ON DERMATOSPARAXIS","volume":"276","author":"Fernandes","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4095","DOI":"10.1093\/hmg\/ddx297","article-title":"Loss of ADAMTS3 Activity Causes Hennekam Lymphangiectasia\u2013Lymphedema Syndrome 3","volume":"26","author":"Brouillard","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4916","DOI":"10.1038\/s41598-017-04982-1","article-title":"Efficient Activation of the Lymphangiogenic Growth Factor VEGF-C Requires the C-Terminal Domain of VEGF-C and the N-Terminal Domain of CCBE1","volume":"7","author":"Jha","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_64","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_65","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_66","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_67","doi-asserted-by":"crossref","first-page":"2680","DOI":"10.1242\/dev.106591","article-title":"Vegfd Can Compensate for Loss of Vegfc in Zebrafish Facial Lymphatic Sprouting","volume":"141","author":"Astin","year":"2014","journal-title":"Development"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"19166","DOI":"10.1074\/jbc.M100097200","article-title":"The Specificity of Receptor Binding by Vascular Endothelial Growth Factor-D Is Different in Mouse and Man","volume":"276","author":"Baldwin","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_69","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_70","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_71","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1182\/blood.2020005699","article-title":"VEGF-C Protects the Integrity of Bone Marrow Perivascular Niche","volume":"136","author":"Fang","year":"2020","journal-title":"Blood"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1182\/blood-2015-12-687970","article-title":"Critical Requirement of VEGF-C in Transition to Fetal Erythropoiesis","volume":"128","author":"Fang","year":"2016","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Hasselhof, V., Sperling, A., Buttler, K., Str\u00f6bel, P., Becker, J., Aung, T., Felmerer, G., and Wilting, J. (2016). Morphological and Molecular Characterization of Human Dermal Lymphatic Collectors. PLOS ONE, 11.","DOI":"10.1371\/journal.pone.0164964"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1387\/ijdb.113394jf","article-title":"Ccbe1 Expression Marks the Cardiac and Lymphatic Progenitor Lineages during Early Stages of Mouse Development","volume":"55","author":"Bento","year":"2011","journal-title":"Int. J. Dev. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/S0002-9440(10)64255-1","article-title":"Tumor-Associated Macrophages Express Lymphatic Endothelial Growth Factors and Are Related to Peritumoral Lymphangiogenesis","volume":"161","author":"Schoppmann","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nm.1960","article-title":"Macrophages Regulate Salt-Dependent Volume and Blood Pressure by a Vascular Endothelial Growth Factor-C\u2013Dependent Buffering Mechanism","volume":"15","author":"Machnik","year":"2009","journal-title":"Nat. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/2045-824X-4-15","article-title":"Deciphering the Roles of Macrophages in Developmental and Inflammation Stimulated Lymphangiogenesis","volume":"4","author":"Harvey","year":"2012","journal-title":"Vasc. Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0925-4773(01)00510-X","article-title":"The Drosophila VEGF Receptor Homolog Is Expressed in Hemocytes","volume":"109","author":"Heino","year":"2001","journal-title":"Mech. Dev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1002\/dvdy.20139","article-title":"Homologs of Vascular Endothelial Growth Factor and Receptor, VEGF and VEGFR, in the Jellyfish Podocoryne carnea","volume":"231","author":"Seipel","year":"2004","journal-title":"Dev. Dyn."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1096\/fj.05-4147com","article-title":"The C. Elegans Pvf-1 Gene Encodes a PDGF\/VEGF-like Factor Able to Bind Mammalian VEGF Receptors and to Induce Angiogenesis","volume":"20","author":"Tarsitano","year":"2006","journal-title":"FASEB J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1007\/PL00006165","article-title":"Extraordinary Conservation of Cysteines Among Homologous Chironomus Silk Proteins Sp185 and Sp220","volume":"44","author":"Case","year":"1997","journal-title":"J. Mol. Evol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1161\/CIRCRESAHA.116.308504","article-title":"Functional Importance of a Proteoglycan Co-Receptor in Pathologic Lymphangiogenesis","volume":"119","author":"Johns","year":"2016","journal-title":"Circ. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1161\/01.RES.0000269042.58594.f6","article-title":"Enhanced Capillary Formation Stimulated by a Chimeric Vascular Endothelial Growth Factor\/Vascular Endothelial Growth Factor-C Silk Domain Fusion Protein","volume":"100","author":"Keskitalo","year":"2007","journal-title":"Circ. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1161\/01.RES.0000269043.51272.6d","article-title":"Distinct Architecture of Lymphatic Vessels Induced by Chimeric Vascular Endothelial Growth Factor-C\/Vascular Endothelial Growth Factor Heparin-Binding Domain Fusion Proteins","volume":"100","author":"Tammela","year":"2007","journal-title":"Circ. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1080\/10408360490460933","article-title":"Latent TGF-Beta Binding Proteins: Extracellular Matrix Association and Roles in TGF-Beta Activation","volume":"41","author":"Penttinen","year":"2004","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"32127","DOI":"10.1074\/jbc.274.45.32127","article-title":"Biosynthesis of Vascular Endothelial Growth Factor-D Involves Proteolytic Processing Which Generates Non-Covalent Homodimers","volume":"274","author":"Stacker","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1182\/blood-2010-08-301549","article-title":"Structural Determinants of Vascular Endothelial Growth Factor-D Receptor Binding and Specificity","volume":"117","author":"Leppanen","year":"2011","journal-title":"Blood"},{"key":"ref_88","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_89","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_90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/pros.20101","article-title":"Substrates of the Prostate-Specific Serine Protease Prostase\/KLK4 Defined by Positional-Scanning Peptide Libraries","volume":"62","author":"Matsumura","year":"2005","journal-title":"Prostate"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Gupta, N., Sudhakar, D.V.S., Gangwar, P.K., Sankhwar, S.N., Gupta, N.J., Chakraborty, B., Thangaraj, K., Gupta, G., and Rajender, S. (2017). Mutations in the Prostate Specific Antigen (PSA\/KLK3) Correlate with Male Infertility. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-10866-1"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1042\/BJ20041424","article-title":"Semenogelins I and II Bind Zinc and Regulate the Activity of Prostate-Specific Antigen","volume":"387","author":"Jonsson","year":"2005","journal-title":"Biochem. J."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/S0022-5347(01)67114-3","article-title":"Vascular Permeability Factor (Vascular Endothelial Growth Factor) Is Strongly Expressed in the Normal Male Genital Tract and Is Present in Substantial Quantities in Semen","volume":"154","author":"Brown","year":"1995","journal-title":"J. Urol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0015-0282(99)00234-4","article-title":"Vascular Endothelial Growth Factor and Its Receptors in Male Fertility","volume":"72","author":"Obermair","year":"1999","journal-title":"Fertil. Steril."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.rbmo.2009.09.019","article-title":"Effect of Vascular Endothelial Growth Factor on Sperm Motility and Survival","volume":"19","author":"Iyibozkurt","year":"2009","journal-title":"Reprod. Biomed. Online"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1096\/fj.04-1592fje","article-title":"Vascular Endothelial Growth Factor-C Gene Therapy Restores Lymphatic Flow across Incision Wounds","volume":"18","author":"Saaristo","year":"2004","journal-title":"FASEB J."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.2353\/ajpath.2006.051251","article-title":"Vascular Endothelial Growth Factor-C Accelerates Diabetic Wound Healing","volume":"169","author":"Saaristo","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1210\/er.2009-0034","article-title":"Kallikreins on Steroids: Structure, Function, and Hormonal Regulation of Prostate-Specific Antigen and the Extended Kallikrein Locus","volume":"31","author":"Lawrence","year":"2010","journal-title":"Endocr. Rev."},{"key":"ref_99","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_100","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1126\/science.276.5317.1423","article-title":"Hyperplasia of Lymphatic Vessels in VEGF-C Transgenic Mice","volume":"276","author":"Jeltsch","year":"1997","journal-title":"Science"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Kr\u00e4usslich, H.-G., and Bartenschlager, R. (2009). Viral Protease Inhibitors. Antiviral Strategies, Springer. Handbook of Experimental Pharmacology.","DOI":"10.1007\/978-3-540-79086-0"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.chest.2017.03.056","article-title":"The Role of Neutrophil Elastase Inhibitors in Lung Diseases","volume":"152","author":"Polverino","year":"2017","journal-title":"Chest"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.ehj.2004.06.003","article-title":"Expert Consensus Document on Angiotensin Converting Enzyme Inhibitors in Cardiovascular Disease: The Task Force on ACE-Inhibitors of the European Society of Cardiology","volume":"25","author":"Swedberg","year":"2004","journal-title":"Eur. Heart J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1016\/S0140-6736(12)60738-7","article-title":"Recombinant Tissue Plasminogen Activator for Acute Ischaemic Stroke: An Updated Systematic Review and Meta-Analysis","volume":"379","author":"Wardlaw","year":"2012","journal-title":"Lancet"},{"key":"ref_105","first-page":"96","article-title":"Die lymphangiogenen Wachstumsfaktoren VEGF-C und VEGF-D. Teil 2. Die Rolle von VEGF-C und VEGF-D bei Krankheiten des Lymphgef\u00e4\u00dfsystems","volume":"17","author":"Krebs","year":"2013","journal-title":"Lymphol. Forsch. Prax."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1016\/j.bjps.2020.05.009","article-title":"Phase 1 Lymfactin\u24c7 Study: Short-Term Safety of Combined Adenoviral VEGF-C and Lymph Node Transfer Treatment for Upper Extremity Lymphedema","volume":"73","author":"Hartiala","year":"2020","journal-title":"J. Plast. Reconstr. Aesthet. Surg."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"12187","DOI":"10.1074\/jbc.M511593200","article-title":"Vascular Endothelial Growth Factor (VEGF)\/VEGF-C Mosaic Molecules Reveal Specificity Determinants and Feature Novel Receptor Binding Patterns","volume":"281","author":"Jeltsch","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1021\/bi401518b","article-title":"Mechanism of Dimerization of a Recombinant Mature Vascular Endothelial Growth Factor C","volume":"53","author":"Chiu","year":"2014","journal-title":"Biochemistry"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Suh, S.H., Choe, K., Hong, S.P., Jeong, S., M\u00e4kinen, T., Kim, K.S., Alitalo, K., Surh, C.D., Koh, G.Y., and Song, J.-H. (2019). Gut Microbiota Regulates Lacteal Integrity by Inducing VEGF-C in Intestinal Villus Macrophages. EMBO Rep., 20.","DOI":"10.15252\/embr.201846927"},{"key":"ref_110","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":"J. Exp. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"H709","DOI":"10.1152\/ajpheart.00102.2007","article-title":"Vascular Endothelial Growth Factor-C Stimulates the Lymphatic Pump by a VEGF Receptor-3-Dependent Mechanism","volume":"293","author":"Breslin","year":"2007","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_112","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_113","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/s41467-020-14921-w","article-title":"Efficient Homing of T Cells via Afferent Lymphatics Requires Mechanical Arrest and Integrin-Supported Chemokine Guidance","volume":"11","author":"Martens","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Jackson, D.G. (2019). Leucocyte Trafficking via the Lymphatic Vasculature\u2014 Mechanisms and Consequences. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00471"},{"key":"ref_115","first-page":"1786","article-title":"Vascular Endothelial Growth Factor C Promotes Tumor Lymphangiogenesis and Intralymphatic Tumor Growth","volume":"61","author":"Karpanen","year":"2001","journal-title":"Cancer Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1093\/emboj\/20.4.672","article-title":"Vascular Endothelial Growth Factor-C-Mediated Lymphangiogenesis Promotes Tumour Metastasis","volume":"20","author":"Mandriota","year":"2001","journal-title":"EMBO J."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/84643","article-title":"Induction of Tumor Lymphangiogenesis by VEGF-C Promotes Breast Cancer Metastasis","volume":"7","author":"Skobe","year":"2001","journal-title":"Nat. Med."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.coi.2018.04.008","article-title":"The Evolving Role of Lymphatics in Cancer Metastasis","volume":"53","author":"Farnsworth","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/nrc745","article-title":"New Functions for the Matrix Metalloproteinases in Cancer Progression","volume":"2","author":"Egeblad","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1160\/TH05-01-0054","article-title":"Plasminogen Activation and Cancer","volume":"93","author":"Behrendt","year":"2005","journal-title":"Thromb. Haemost."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1096\/fj.10-179788","article-title":"Proteolytic Processing of Vascular Endothelial Growth Factor-D Is Essential for Its Capacity to Promote the Growth and Spread of Cancer","volume":"25","author":"Harris","year":"2011","journal-title":"FASEB J."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"4499","DOI":"10.1038\/onc.2011.602","article-title":"Interaction of Tumor Cells and Lymphatic Vessels in Cancer Progression","volume":"31","author":"Alitalo","year":"2012","journal-title":"Oncogene"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1093\/neuonc\/noy103","article-title":"VEGF-C Sustains VEGFR2 Activation under Bevacizumab Therapy and Promotes Glioblastoma Maintenance","volume":"20","author":"Michaelsen","year":"2018","journal-title":"Neuro-Oncol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nrc2442","article-title":"Modes of Resistance to Anti-Angiogenic Therapy","volume":"8","author":"Bergers","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"661","DOI":"10.7150\/thno.27794","article-title":"VEGFC Acts as a Double-Edged Sword in Renal Cell Carcinoma Aggressiveness","volume":"9","author":"Ndiaye","year":"2019","journal-title":"Theranostics"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"eaal4712","DOI":"10.1126\/scitranslmed.aal4712","article-title":"Tumor Lymphangiogenesis Promotes T Cell Infiltration and Potentiates Immunotherapy in Melanoma","volume":"9","author":"Fankhauser","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_127","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_128","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.jaad.2017.03.022","article-title":"Lymphedema: Pathophysiology and Clinical Manifestations","volume":"77","author":"Grada","year":"2017","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_129","unstructured":"Weissleder, H., and Schuchhardt, C. (2015). Die genetischen Ursachen des prim\u00e4ren Lymph\u00f6dems. Erkrankungen des Lymphgef\u00e4\u00dfsystems, Viavital Verlag."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1136\/jmedgenet-2019-106084","article-title":"Update and Audit of the St George\u2019s Classification Algorithm of Primary Lymphatic Anomalies: A Clinical and Molecular Approach to Diagnosis","volume":"57","author":"Gordon","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1089\/lrb.2011.0024","article-title":"Possible Genetic Predisposition to Lymphedema after Breast Cancer","volume":"10","author":"Newman","year":"2012","journal-title":"Lymphat. Res. Biol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1089\/lrb.2008.1524","article-title":"HGF and MET Mutations in Primary and Secondary Lymphedema","volume":"6","author":"Finegold","year":"2008","journal-title":"Lymphat. Res. Biol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1158\/1078-0432.CCR-11-2303","article-title":"Connexin 47 Mutations Increase Risk for Secondary Lymphedema Following Breast Cancer Treatment","volume":"18","author":"Finegold","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_134","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_135","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/humu.22223","article-title":"FLT4\/VEGFR3 and Milroy Disease: Novel Mutations, a Review of Published Variants and Database Update","volume":"34","author":"Gordon","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1161\/CIRCRESAHA.113.300350","article-title":"Mutation in Vascular Endothelial Growth Factor-C, a Ligand for Vascular Endothelial Growth Factor Receptor-3, Is Associated With Autosomal Dominant Milroy-Like Primary Lymphedema. Novelty and Significance","volume":"112","author":"Gordon","year":"2013","journal-title":"Circ. Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1136\/jmedgenet-2013-102020","article-title":"A Novel Stop Mutation in the Vascular Endothelial Growth Factor-C Gene (VEGFC) Results in Milroy-like Disease","volume":"51","author":"Lago","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00439-009-0766-y","article-title":"Linkage and Sequence Analysis Indicate That CCBE1 Is Mutated in Recessively Inherited Generalised Lymphatic Dysplasia","volume":"127","author":"Connell","year":"2010","journal-title":"Hum. Genet."},{"key":"ref_139","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_140","first-page":"1585","article-title":"Comparative Integromics on VEGF Family Members","volume":"28","author":"Katoh","year":"2006","journal-title":"Int. J. Oncol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3389\/fbioe.2018.00007","article-title":"Biology of Vascular Endothelial Growth Factor C in the Morphogenesis of Lymphatic Vessels","volume":"6","author":"Rauniyar","year":"2018","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.jsams.2013.02.006","article-title":"Polymorphic Variation within the ADAMTS2, ADAMTS14, ADAMTS5, ADAM12 and TIMP2 Genes and the Risk of Achilles Tendon Pathology: A Genetic Association Study","volume":"16","author":"Posthumus","year":"2013","journal-title":"J. Sci. Med. Sport"},{"key":"ref_143","first-page":"61","article-title":"PSA (Prostate-Specific Antigen) and other Kallikrein-related Peptidases in Prostate Cancer","volume":"Volume 2","author":"Magdolen","year":"2012","journal-title":"Kallikrein-Related Peptidase. Novel Cancer Related Biomarkers"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1093\/brain\/awl107","article-title":"Cathepsin D Deficiency Underlies Congenital Human Neuronal Ceroid-Lipofuscinosis","volume":"129","author":"Siintola","year":"2006","journal-title":"Brain"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1056\/NEJM200104193441607","article-title":"Genetic Susceptibility to Venous Thrombosis","volume":"344","author":"Seligsohn","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1055\/s-2004-822971","article-title":"Role of Thrombin in Angiogenesis and Tumor Progression","volume":"30","author":"Tsopanoglou","year":"2004","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S0039-6257(03)00056-0","article-title":"Ligneous Conjunctivitis","volume":"48","author":"Schuster","year":"2003","journal-title":"Surv. Ophthalmol."},{"key":"ref_148","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_149","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":"Ivanov","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.ajhg.2010.04.010","article-title":"GJC2 Missense Mutations Cause Human Lymphedema","volume":"86","author":"Ferrell","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1038\/ng.2765","article-title":"Mutations in Genes Encoding the Cadherin Receptor-Ligand Pair DCHS1 and FAT4 Disrupt Cerebral Cortical Development","volume":"45","author":"Cappello","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Frangoul, H., Altshuler, D., Cappellini, M.D., Chen, Y.-S., Domm, J., Eustace, B.K., Foell, J., de la Fuente, J., Grupp, S., and Handgretinger, R. (2020). CRISPR-Cas9 Gene Editing for Sickle Cell Disease and \u03b2-Thalassemia. N. Engl. J. Med.","DOI":"10.1530\/ey.18.14.4"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/d41586-020-00655-8","article-title":"CRISPR Treatment Inserted Directly into the Body for First Time","volume":"579","author":"Ledford","year":"2020","journal-title":"Nature"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1007\/s13346-017-0464-6","article-title":"Targeting Therapeutics to Endothelium: Are We There Yet?","volume":"8","author":"Kiseleva","year":"2018","journal-title":"Drug Deliv. Transl. 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