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.
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
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 |