University of Oulu

Korhonen, E. A., Murtomäki, A., Jha, S. K., Anisimov, A., Pink, A., Zhang, Y., Stritt, S., Liaqat, I., Stanczuk, L., Alderfer, L., Sun, Z., Kapiainen, E., Singh, A., Sultan, I., Lantta, A., Leppänen, V.-M., Eklund, L., He, Y., Augustin, H. G., … Alitalo, K. (2022). Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression. Journal of Clinical Investigation, 132(15), e155478.

Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

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Author: Korhonen, Emilia A.1,2; Murtomäki, Aino1,2; Jha, Sawan Kumar1,2;
Organizations: 1Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
2Translational Cancer Medicine Program, University of Helsinki, Helsinki, Finland
3Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
4Bioengineering Graduate Program, University of Notre Dame, South Bend, Indiana, USA
5Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Cam-Su Genomic Resources Center, Soochow University, Suzhou, China
6Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
7Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
8European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
9iCAN Digital Precision Cancer Medicine Flagship, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 29.5 MB)
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Language: English
Published: American Society for Clinical Investigation, 2022
Publish Date: 2022-10-20


Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor 3 (VEGFR3), which is encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development, and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here, we used gene deletion, blocking Abs, transgene induction, and gene transfer to study how Ang2, its Tie2 receptor, and Tie1 regulate lymphatic vessels. We discovered that VEGF-C–induced Ang2 secretion from lymphatic endothelial cells (LECs) was involved in full Akt activation downstream of phosphoinositide 3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of an Ang2-blocking Ab decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of the PI3K catalytic p110α subunit or with small-molecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C–induced lymphangiogenesis also in adult mice. Our results reveal an important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2/Tie/PI3K signaling.

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Series: Journal of clinical investigation
ISSN: 0021-9738
ISSN-E: 1558-8238
ISSN-L: 0021-9738
Volume: 132
Issue: 15
Article number: e155478
DOI: 10.1172/jci155478
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was funded by the Wihuri Foundation (to KA, EAK, AM, SKJ, AA, VML, IS, PS, and KV); the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 874708 (THERALYMPH, to KA) and 773076 (to PS); the Novo Nordisk Foundation (grant NNF16OC0023554, to KA); the Sigrid Jusélius Foundation (to KA, PS, KV, and LE); the Hospital District of Helsinki and the Uusimaa Research Grant (to KA); the Cancer Foundation Finland (to KA and PS); the Academy of Finland Centre of Excellence Program (307366, to KA); the Academy of Finland Research Costs of Academy Professor (312516, to KA); the Maud Kuistila Memorial Foundation (to EAK); the Ida Montini Foundation (to EAK); The Priority Academic Program Development of Jiangsu Higher Education Institutions (to YH); the National Natural Science Foundation of China (31970768, to YH); the Knut and Alice Wallenberg Foundation (2018.0218, to TM); the Swedish Research Council (2020-02692, to TM); the Academy of Finland (310986, to LE; 310075, to PS); the Academy of Finland Academy Fellow Funding (315710, to KV); and the European Research Council Advanced Grant Angiomature (project 787181, to HGA).
Academy of Finland Grant Number: 310986
Detailed Information: 310986 (Academy of Finland Funding decision)
Copyright information: © 2022, Korhonen et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.