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 ErdmannAdmar Verschoor, Emmanouil Chavakis, Triantafyllos Chavakis, Philipp von Hundelshausen, Jörg Köhl, Meinrad Gawaz, Harald F. Langer*

*Corresponding author for this work


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.

Original languageEnglish
Article number3352
JournalNature Communications
Issue number1
Pages (from-to)3352
Publication statusPublished - 12.2021

Research Areas and Centers

  • Centers: Cardiological Center Luebeck (UHZL)

DFG Research Classification Scheme

  • 205-12 Cardiology, Angiology


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