The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets

Henry Nording, Lasse Baron, David Haberthür, Frederic Emschermann, Matthias Mezger, Manuela Sauter, Reinhard Sauter, Johannes Patzelt, Kai Knoepp, Anne Nording, Moritz Meusel, Roza Meyer-Saraei, Ruslan Hlushchuk, Daniel Sedding, Oliver Borst, Ingo Eitel, Christian M. Karsten, Robert Feil, Bernd Pichler, Jeanette Erdmann, Admar Verschoor, Emmanouil Chavakis, Triantafyllos Chavakis, Philipp Hundelshausen, Jörg Köhl, Meinrad Gawaz and Harald F. Langer ()
Additional contact information
Henry Nording: University Heart Center Lübeck
Lasse Baron: University Heart Center Lübeck
David Haberthür: University of Bern
Frederic Emschermann: Eberhard Karls University
Matthias Mezger: University Heart Center Lübeck
Manuela Sauter: University Heart Center Lübeck
Reinhard Sauter: University Heart Center Lübeck
Johannes Patzelt: University Heart Center Lübeck
Kai Knoepp: Martin-Luther-University Halle (Saale)
Anne Nording: Eberhard Karls University
Moritz Meusel: University Heart Center Lübeck
Roza Meyer-Saraei: DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel
Ruslan Hlushchuk: University of Bern
Daniel Sedding: Martin-Luther-University Halle (Saale)
Oliver Borst: Eberhard Karls University
Ingo Eitel: DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel
Christian M. Karsten: University of Lübeck
Robert Feil: University of Tübingen
Bernd Pichler: Eberhard Karls University
Jeanette Erdmann: DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel
Admar Verschoor: University of Lübeck
Emmanouil Chavakis: University Hospital of the Johann-Wolfgang Goethe University
Triantafyllos Chavakis: Technische Universität Dresden
Philipp Hundelshausen: Ludwig Maximilians University Munich
Jörg Köhl: University of Lübeck
Meinrad Gawaz: Eberhard Karls University
Harald F. Langer: University Heart Center Lübeck

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: Abstract Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1−/− mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo. In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23499-w

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DOI: 10.1038/s41467-021-23499-w

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