Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Citations to this article

Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD
Hung M. Bui, … , Kari Alitalo, Mark L. Kahn
Hung M. Bui, … , Kari Alitalo, Mark L. Kahn
Published May 9, 2016
Citation Information: J Clin Invest. 2016;126(6):2167-2180. https://doi.org/10.1172/JCI83967.
View: Text | PDF
Research Article Vascular biology Article has an altmetric score of 3

Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD

  • Text
  • PDF
Abstract

Lymphangiogenesis is supported by 2 homologous VEGFR3 ligands, VEGFC and VEGFD. VEGFC is required for lymphatic development, while VEGFD is not. VEGFC and VEGFD are proteolytically cleaved after cell secretion in vitro, and recent studies have implicated the protease a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3) and the secreted factor collagen and calcium binding EGF domains 1 (CCBE1) in this process. It is not well understood how ligand proteolysis is controlled at the molecular level or how this process regulates lymphangiogenesis, because these complex molecular interactions have been difficult to follow ex vivo and test in vivo. Here, we have developed and used biochemical and cellular tools to demonstrate that an ADAMTS3-CCBE1 complex can form independently of VEGFR3 and is required to convert VEGFC, but not VEGFD, into an active ligand. Consistent with these ex vivo findings, mouse genetic studies revealed that ADAMTS3 is required for lymphatic development in a manner that is identical to the requirement of VEGFC and CCBE1 for lymphatic development. Moreover, CCBE1 was required for in vivo lymphangiogenesis stimulated by VEGFC but not VEGFD. Together, these studies reveal that lymphangiogenesis is regulated by two distinct proteolytic mechanisms of ligand activation: one in which VEGFC activation by ADAMTS3 and CCBE1 spatially and temporally patterns developing lymphatics, and one in which VEGFD activation by a distinct proteolytic mechanism may be stimulated during inflammatory lymphatic growth.

Authors

Hung M. Bui, David Enis, Marius R. Robciuc, Harri J. Nurmi, Jennifer Cohen, Mei Chen, Yiqing Yang, Veerpal Dhillon, Kathy Johnson, Hong Zhang, Robert Kirkpatrick, Elizabeth Traxler, Andrey Anisimov, Kari Alitalo, Mark L. Kahn

×

Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2010 Total
Citations: 5 7 6 10 10 10 11 6 6 1 72
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article (72)

Title and authors Publication Year
Clinical Progress of Fruquintinib in Colorectal Cancer: An Overview
Xie Y, Tang S, Qin Z, Yang C
Pharmaceuticals 2025
Regulation of VEGFR3 signaling in lymphatic endothelial cells
Kuonqui KG, Campbell AC, Pollack BL, Shin J, Sarker A, Brown S, Park HJ, Mehrara BJ, Kataru RP
Frontiers in Cell and Developmental Biology 2025
Extracellular vesicles-miR-205-5p inhibits lymphatic metastasis in pancreatic cancer through diffusely downregulating VEGFA
Wang Y, Qin C, Zhao Y, Zhao B, Li Z, Li T, Zhang X, Wang W
Journal of Cancer 2025
Meningeal lymphatic drainage: novel insights into central nervous system disease.
Zhang Q, Niu Y, Li Y, Xia C, Chen Z, Chen Y, Feng H
Signal transduction and targeted therapy 2025
Genetic Polymorphisms of Vascular Endothelial Growth Factor and Their Impact on Recurrent Spontaneous Miscarriage in Saudi Women
Al-Qahtani WK, Alkhuriji AF, Babay ZA, Kaabi AM, Al-Malahi NM, Alshammari JO
International Journal of Molecular Sciences 2025
Central Conducting Lymphatic Anomaly: From bench to bedside
Luciana Daniela Garlisi Torales, Benjamin Sempowski, Georgia Krikorian, Sarah E. Sheppard
Journal of Clinical Investigation 2024
Digital spatial profiling of segmental outflow regions in trabecular meshwork reveals a role for ADAM15
Faralli JA, Filla MS, Yang YF, Sun YY, Johns K, Keller KE, Peters DM
PloS one 2024
Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression
Mondal DK, Xie C, Pascal GJ, Buraschi S, Iozzo RV
Proceedings of the National Academy of Sciences 2024
Generation and characterisation of scalable and stable human pluripotent stem cell-derived microvascular-like endothelial cells for cardiac applications.
Majid QA, Ghimire BR, Merkely B, Randi AM, Harding SE, Talman V, Földes G
Angiogenesis 2024
Molecular pathophysiology of secondary lymphedema.
Lee SO, Kim IK
Frontiers in Cell and Developmental Biology 2024
Differential vegfc expression dictates lymphatic response during zebrafish heart development and regeneration
Duca S, Xia Y, Abd Elmagid L, Bakis I, Qiu M, Cao Y, Guo Y, Eichenbaum JV, McCain ML, Kang J, Harrison MR, Cao J
Development (Cambridge, England) 2024
Therapeutically Induced Lymphangiogenesis Is Ineffective in Resolving Established Kidney Disease in Mice.
Kannan S, Phan TT, Creed HA, Reyna AJ, Baranwal G, Rich AL, Weiss DL, Rutkowski JM
Kidney360 2024
Breaking a Vicious Circle: Lymphangiogenesis as a New Therapeutic Target in Wound Healing
Renò F, Sabbatini M
Biomedicines 2023
Evaluation of Fruquintinib in the Continuum of Care of Patients with Colorectal Cancer
Lavacchi D, Roviello G, Guidolin A, Romano S, Venturini J, Caliman E, Vannini A, Giommoni E, Pellegrini E, Brugia M, Pillozzi S, Antonuzzo L
International journal of molecular sciences 2023
Modeling Lymphangiogenesis: Pairing in vitro and in vivo metrics
Suarez AC, Hammel JH, Munson JM
Microcirculation (New York, N.Y. : 1994) 2023
Dual FGFR and VEGFR inhibition synergistically restrain hexokinase 2-dependent lymphangiogenesis and immune escape in intrahepatic cholangiocarcinoma.
Peng M, Li H, Cao H, Huang Y, Yu W, Shen C, Gu J
Journal of Gastroenterology 2023
The Sympathetic Nervous System Promotes Hepatic Lymphangiogenesis, which Is Protective Against Liver Fibrosis
Tanaka M, Jeong J, Thomas C, Zhang X, Zhang P, Saruwatari J, Kondo R, McConnell MJ, Utsumi T, Iwakiri Y
The American Journal of Pathology 2023
Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function
Carter EP, Yoneten KK, Gavara N, Tyler EJ, Gauthier V, Murray ER, ten Dijke P, Cameron AJ, Pearce O, Grose RP
The Journal of Pathology 2023
CCBE1 in Cardiac Development and Disease
F Bonet, J Inácio, O Bover, S Añez, J Belo
Frontiers in Genetics 2022
Proper migration of lymphatic endothelial cells requires survival and guidance cues from arterial mural cells
D Peng, K Ando, M Hußmann, M Gloger, R Skoczylas, N Mochizuki, C Betsholtz, S Fukuhara, S Schulte-Merker, N Lawson, K Koltowska
eLife 2022
Lymphangiogenesis: A new player in the heart's adaptive response to exercise
Dozic S, Janssens JV, Weeks KL
Journal of Sport and Health Science 2022
Combination of sunitinib and 177Lu-labeled antibody cG250 targeted radioimmunotherapy: A promising new therapeutic strategy for patients with advanced renal cell cancer
Oosterwijk-Wakka JC, de Weijert MC, Franssen GM, Kolev DR, de Haan TA, Boerman OC, Mulders PF, Oosterwijk E
Neoplasia (New York, N.Y.) 2022
Suppression of VEGFD expression by S-nitrosylation promotes the development of lung adenocarcinoma
He Q, Qu M, Shen T, Xu Y, Luo J, Tan D, Xu C, Barkat MQ, Zeng LH, Wu X
Journal of experimental & clinical cancer research : CR 2022
miR-31-5p-Modified RAW 264.7 Macrophages Affect Profibrotic Phenotype of Lymphatic Endothelial Cells In Vitro
Moskalik A, Ratajska A, Majchrzak B, Jankowska-Steifer E, Bartkowiak K, Bartkowiak M, Niderla-Bielińska J
International journal of molecular sciences 2022
Hepatic lymphatic vascular system in health and disease
Jeong J, Tanaka M, Iwakiri Y
Journal of Hepatology 2022
Downregulation of ADAMTS3 Suppresses Stemness and Tumorigenicity in Glioma Stem Cell
Kim H, Jeong HY, Batara DC, Moon C, Lee S, Lee SJ, Park S, Choi M, Kim S
CNS Neuroscience & Therapeutics 2022
Sinusoidal and lymphatic vessel growth is controlled by reciprocal VEGF-C–CDH5 inhibition
Sung DC, Chen M, Dominguez MH, Mahadevan A, Chen X, Yang J, Gao S, Ren AA, Tang AT, Mericko P, Patton R, Lee M, Jannaway M, Nottebaum A, Vestweber D, Scallan JP, Kahn ML
2022
Molecular Mechanisms Driving Lymphedema and Other Lymphatic Anomalies
Geng X, Srinivasan RS
Cold Spring Harbor Perspectives in Medicine 2022
Nucleoside-modified VEGFC mRNA induces organ-specific lymphatic growth and reverses experimental lymphedema
D Szőke, G Kovács, É Kemecsei, L Bálint, K Szoták-Ajtay, P Aradi, AS Dinnyés, BL Mui, YK Tam, TD Madden, K Karikó, RP Kataru, MJ Hope, D Weissman, BJ Mehrara, N Pardi, Z Jakus
Nature Communications 2021
Interplay between Gut Lymphatic Vessels and Microbiota
E Solari, C Marcozzi, D Negrini, A Moriondo
Cells 2021
Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease: An Update
GA Secker, NL Harvey
International journal of molecular sciences 2021
Biochemical and mechanical signals in the lymphatic vasculature
X Geng, YC Ho, RS Srinivasan
Cellular and Molecular Life Sciences 2021
Role of Vascular Endothelial Growth Factor (VEGF) in Human Embryo Implantation: Clinical Implications
, H Yi, TC Li, Y Wang, H Wang, X Chen
Biomolecules 2021
Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs
J Künnapuu, H Bokharaie, M Jeltsch
Biology : open access journal 2021
Cerebrovascular development: mechanisms and experimental approaches
TJ Chico, EC Kugler
Cellular and Molecular Life Sciences 2021
Mechanisms and cell lineages in lymphatic vascular development
DJ Jafree, DA Long, PJ Scambler, C Ruhrberg
Angiogenesis 2021
Systemic Interleukins’ Profile in Early and Advanced Colorectal Cancer
P Czajka-Francuz, S Cisoń-Jurek, A Czajka, M Kozaczka, J Wojnar, J Chudek, T Francuz
International journal of molecular sciences 2021
KLK3 in the Regulation of Angiogenesis—Tumorigenic or Not?
H Koistinen, J Künnapuu, M Jeltsch
International journal of molecular sciences 2021
Lymphatic Proliferation Ameliorates Pulmonary Fibrosis after Lung Injury
P Baluk, RP Naikawadi, S Kim, F Rodriguez, D Choi, YK Hong, PJ Wolters, DM McDonald
The American Journal of Pathology 2020
Emerging Role of Lymphatics in the Regulation of Intestinal Lipid Mobilization
C Xiao, P Stahel, A Nahmias, GF Lewis
Frontiers in physiology 2020
The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease
G Oliver, J Kipnis, GJ Randolph, NL Harvey
Cell 2020
DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination
CA Wang, IH Chang, PC Hou, YJ Tai, WN Li, PL Hsu, SR Wu, WT Chiu, CF Li, YS Shan, SJ Tsai
Journal of Extracellular Vesicles 2020
Specific fibroblast subpopulations and neuronal structures provide local sources of Vegfc-processing components during zebrafish lymphangiogenesis
G Wang, L Muhl, Y Padberg, L Dupont, J Peterson-Maduro, M Stehling, F le Noble, A Colige, C Betsholtz, S Schulte-Merker, A van Impel
Nature Communications 2020
Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis
L Gutierrez-Miranda, K Yaniv
Frontiers in physiology 2020
Structural Basis for Vascular Endothelial Growth Factor Receptor Activation and Implications for Disease Therapy
F Shaik, G Cuthbert, S Homer-Vanniasinkam, S Muench, S Ponnambalam, M Harrison
Biomolecules 2020
Lymphatic Vasculature in Energy Homeostasis and Obesity
YC Ho, RS Srinivasan
Frontiers in physiology 2020
CCBE1 promotes tumor lymphangiogenesis and is negatively regulated by TGFβ signaling in colorectal cancer
J Song, W Chen, X Cui, Z Huang, D Wen, Y Yang, W Yu, L Cui, CY Liu
Theranostics 2020
Investigation on the role of biallelic variants in VEGF‐C found in a patient affected by Milroy‐like lymphedema
S Mukenge, SK Jha, M Catena, E Manara, VM Leppänen, E Lenti, D Negrini, M Bertelli, A Brendolan, M Jeltsch, L Aldrighetti
Molecular Genetics & Genomic Medicine 2020
Gut microbiota regulates lacteal integrity by inducing VEGF‐C in intestinal villus macrophages
SH Suh, K Choe, SP Hong, S Jeong, T Mäkinen, KS Kim, K Alitalo, CD Surh, GY Koh, JH Song
EMBO reports 2019
Arterial Lymphatics in Atherosclerosis: Old Questions, New Insights, and Remaining Challenges
Csányi, Singla
Journal of Clinical Medicine 2019

Communication Of Cancer Cells And Lymphatic Vessels In Cancer: Focus On Bladder Cancer


Z Wu, W Ding, J Cai, G Bashir, Y Li, S Wu
OncoTargets and therapy 2019
KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D
SK Jha, K Rauniyar, E Chronowska, K Mattonet, EW Maina, H Koistinen, UH Stenman, K Alitalo, M Jeltsch
eLife 2019
Transcriptional landscape of pulmonary lymphatic endothelial cells during fetal gestation
TA Norman, AC Gower, F Chen, A Fine, VV Kalinichenko
PloS one 2019
Hemostasis stimulates lymphangiogenesis through release and activation of VEGFC
L Lim, H Bui, O Farrelly, J Yang, L Li, D Enis, W Ma, M Chen, G Oliver, JD Welsh, ML Kahn
Blood 2019
MicroRNA-mediated control of developmental lymphangiogenesis
HM Jung, CT Hu, AM Fister, AE Davis, D Castranova, VN Pham, LM Price, BM Weinstein
eLife 2019
Diagnostic Significance of Fibrin Degradation Products and D-Dimer in Patients With Breast Cancer-Related Lymphedema
SH Ryu, SW Min, JH Kim, HJ Jeong, GC Kim, DK Kim, YJ Sim
Annals of Rehabilitation Medicine 2019
Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells
HC Tai, TH Lee, CH Tang, LP Chen, WC Chen, MS Lee, PC Chen, CY Lin, CW Chi, YJ Chen, CT Lai, SS Chen, KW Liao, CH Lee, SW Wang
Marine drugs 2019
An ADAMTS3 missense variant is associated with Norwich Terrier upper airway syndrome
TW Marchant, E Dietschi, U Rytz, P Schawalder, V Jagannathan, SH Rasouliha, C Gurtner, AS Waldvogel, RS Harrington, M Drögemüller, J Kidd, EA Ostrander, A Warr, M Watson, D Argyle, GT Haar, DN Clements, T Leeb, JJ Schoenebeck, GS Barsh
PLoS genetics 2019

Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer


Y Zhang, JY Zou, Z Wang, Y Wang
Cancer management and research 2019
Vascular Endothelial Growth Factor B and Its Signaling
N Lal, K Puri, B Rodrigues
Frontiers in Cardiovascular Medicine 2018
Regulation of Chylomicron Secretion: Focus on Post Assembly Mechanisms
C Xiao, P Stahel, GF Lewis
CMGH Cellular and Molecular Gastroenterology and Hepatology 2018
Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies-A review
M Yamakawa, SJ Doh, SM Santosa, M Montana, EC Qin, H Kong, KY Han, C Yu, MI Rosenblatt, A Kazlauskas, JH Chang, DT Azar
Medicinal Research Reviews 2018
Roles of the TGF-β–VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis
H Kinashi, Y Ito, T Sun, T Katsuno, Y Takei
International journal of molecular sciences 2018
Biology of Vascular Endothelial Growth Factor C in the Morphogenesis of Lymphatic Vessels
K Rauniyar, SK Jha, M Jeltsch
Frontiers in Bioengineering and Biotechnology 2018
Lymphatic Tissue Engineering and Regeneration
L Alderfer, A Wei, D Hanjaya-Putra
Journal of biological engineering 2018
Intestinal lymphatic vasculature: structure, mechanisms and functions
J Bernier-Latmani, TV Petrova
Nature Reviews Gastroenterology & Hepatology 2017
Vascular heterogeneity and specialization in development and disease
M Potente, T Mäkinen
Nature Reviews Molecular Cell Biology 2017
Lymphangiogenesis guidance by paracrine and pericellular factors
K Vaahtomeri, S Karaman, T Mäkinen, K Alitalo
Genes & development 2017
Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1
SK Jha, K Rauniyar, T Karpanen, VM Leppänen, P Brouillard, M Vikkula, K Alitalo, M Jeltsch
Scientific Reports 2017
Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela - and Apj -Deficient Hearts
B Sharma, L Ho, GH Ford, HI Chen, AB Goldstone, YJ Woo, T Quertermous, B Reversade, K Red-Horse
Developmental Cell 2017
Secreted Metalloproteinase ADAMTS-3 Inactivates Reelin
H Ogino, A Hisanaga, T Kohno, Y Kondo, K Okumura, T Kamei, T Sato, H Asahara, H Tsuiji, M Fukata, M Hattori
The Journal of neuroscience : the official journal of the Society for Neuroscience 2017
Comprehensive Physiology
R Terjung
Comprehensive Physiology 2010

← Previous 1 2 3 Next →

Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 1 Wikipedia pages
103 readers on Mendeley
1 readers on CiteULike
See more details