Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions
Open accessAbstract
Primitive lymphatic vessels are remodeled into functionally specialized initial and collecting lymphatics during development. Lymphatic endothelial cell (LEC) junctions in initial lymphatics transform from a zipper-like to a button-like pattern during collecting vessel development, but what regulates this process is largely unknown. Angiopoietin 2 ( Ang2 ) deficiency leads to abnormal lymphatic vessels. Here we found that an ANG2-blocking antibody inhibited embryonic lymphangiogenesis, whereas endothelium-specific ANG2 overexpression induced lymphatic hyperplasia. ANG2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatics. The defective junctions were associated with impaired lymph uptake. In collecting lymphatics, adherens junctions were disrupted, and the vessels leaked upon ANG2 blockade or gene deletion. ANG2 inhibition also suppressed the onset of lymphatic valve formation and subsequent valve maturation. These data identify ANG2 as the first essential regulator of the functionally important interendothelial cell–cell junctions that form during lymphatic development.
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During vascular development, Ang2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatic vessels.
“During vascular development, Ang2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatic vessels20”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [20]
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- Authors
- Zheng, W., Nurmi, H., Appak, S., Sabine, A., Bovay, E., Korhonen, E. A., Orsenigo, F., Lohela, M., D’Amico, G., Holopainen, T., Leow, C. C., Dejana, E., Petrova, T. V., Augustin, H. G., & Alitalo, K.
- Affiliations
- University of Helsinki (FI)
- Centre Hospitalier Universitaire Vaudois (CH)
- University of Milan (IT)
- German Cancer Research Center (DE)
- Corresponding author
- Alitalo, Kari
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2014-07-15
- Volume
- 28
- Issue
- 14
- Pages
- 1592-1603
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC4102766
- OpenAlex
- W2066164950
- Cited by
- 134
- References
- 46
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 7 · 2023: 16 · 2022: 13 · 2021: 12 · 2020: 15 · 2019: 12 · 2018: 12 · 2017: 10 · 2016: 9 · 2015: 9 · 2014: 1
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, cc-by-nc)
- IRIS (submittedVersion, cc-by-nc)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- Funders
- European Commission
- Fondation Leducq (11CVD03)
- Academy of Finland
- Biomedicum Helsinki-säätiö
- Orionin Tutkimussäätiö
- FP7 Ideas: European Research Council (268804)
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
- Health Sciences › Medicine › Surgery › Vascular Malformations and Hemangiomas
- Keywords
- angiopoietin-2, lymphatic endothelial cells, lymphatic development, lymphangiogenesis, lymphoid hyperplasia, VE-cadherin phosphorylation, adherens junctions, lymphatic leakage, lymphatic absorption
- MeSH terms
- Animals, Embryo, Mammalian, Intercellular Junctions, Lymphoid Tissue, Mice, Inbred C57BL, Phosphorylation, Cadherins, Gene Deletion, Lymphangiogenesis, Angiopoietin-2, Endothelial Cells, Mice
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