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Complement-mediated inhibition of neovascularization reveals a point of convergence between innate immunity and angiogenesis
Open accessAbstract
Beyond its role in immunity, complement mediates a wide range of functions in the context of morphogenetic or tissue remodeling processes. Angiogenesis is crucial during tissue remodeling in multiple pathologies; however, the knowledge about the regulation of neovascularization by the complement components is scarce. Here we studied the involvement of complement in pathological angiogenesis. Strikingly, we found that mice deficient in the central complement component C3 displayed increased neovascularization in the model of retinopathy of prematurity (ROP) and in the in vivo Matrigel plug assay. In addition, antibody-mediated blockade of C5, treatment with C5aR antagonist, or C5aR deficiency in mice resulted in enhanced pathological retina angiogenesis. While complement did not directly affect angiogenesis-related endothelial cell functions, we found that macrophages mediated the antiangiogenic activity of complement. In particular, C5a-stimulated macrophages were polarized toward an angiogenesis-inhibitory phenotype, including the up-regulated secretion of the antiangiogenic soluble vascular endothelial growth factor receptor-1. Consistently, macrophage depletion in vivo reversed the increased neovascularization associated with C3- or C5aR deficiency. Taken together, complement and in particular the C5a-C5aR axes are potent inhibitors of angiogenesis.
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“For instance, the anaphylatoxins C3a and C5a have been found to enhance laser-induced CNV in some cases, but may have anti-angiogenic properties in mouse models of retinal hypoxia through the stimulation of mononuclear phagocytes to secrete soluble VEGF receptor 1 that inhibits VEGF [169,170].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [170]
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“…apoptosis in neurons (Mukherjee and Pasinetti, 2001), and can exert an anti-inflammatory effect in pancreatitis (Bhatia et al., 2001), act as a potent inhibitor of angiogenesis (Langer et al., 2010), and is involved in the early priming stages of liver regeneration (Strey et al., 2003).”
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Metadata
- Authors
- Langer, H. F., Chung, K.-J., Orlova, V. V., Choi, E. Y., Kaul, S., Kruhlak, M. J., Alatsatianos, M., DeAngelis, R. A., Roche, P. A., Magotti, P., Li, X., Economopoulou, M., Rafail, S., Lambris, J. D., & Chavakis, T.
- Affiliations
- National Institutes of Health (US)
- University of Pennsylvania (US)
- Corresponding author
- Lambris, John D.
- Chavakis, Triantafyllos
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-11-25
- Volume
- 116
- Issue
- 22
- Pages
- 4395-4403
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2996109
- OpenAlex
- W2165915271
- Cited by
- 176
- References
- 58
- Citations by year
- 2025: 8 · 2024: 8 · 2023: 9 · 2022: 9 · 2021: 8 · 2020: 9 · 2019: 13 · 2018: 15 · 2017: 8 · 2016: 13 · 2015: 16 · 2014: 12 · 2013: 16 · 2012: 14
- FWCI
- 6.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA112162, CA-112162)
- National Institute of Allergy and Infectious Diseases (AI 068730, P01AI068730)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- complement system, neovascularization, pathological angiogenesis, complement C3, C5a, C5a receptor, retinopathy of prematurity, macrophages, macrophage polarization, soluble VEGFR1, antiangiogenic activity, innate immunity, tissue remodeling
- MeSH terms
- Animals, Cell Line, Complement C3, Complement C5, Humans, Immunity, Innate, Infant, Newborn, Macrophages, Mice, Inbred C57BL, Neovascularization, Pathologic, Retina, Retinopathy of Prematurity, Complement C5a, Gene Deletion, Cell Culture Techniques, Vascular Endothelial Growth Factors, Receptor, Anaphylatoxin C5a, Mice
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