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 von Hundelshausen; Jörg Köhl; Meinrad Gawaz; Harald F. Langer

doi:10.1038/s41467-021-23499-w

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

42 Citations (Scopus)

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.

Original language	English
Article number	3352
Journal	Nature Communications
Volume	12
Issue number	1
Pages (from-to)	3352
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-021-23499-w
Publication status	Published - 12.2021

Funding

We thank Sarah Gekeler, Birgit Fehrenbacher, Jacob von Esebeck, and Anke Constantz for excellent technical assistance. We also thank Jennifer Axnick and Eckhard Lammert for technical assistance with the hindbrain staining. This work was supported by the Volkswagen Foundation (Lichtenberg program), the German Heart Foundation, the Wilhelm Sander Foundation (to H.F.L), the KFO 274 – Platelets – basic mechanisms and clinical implications, and the DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel (STO Projekt F280404). M.G. and H.F.L. are members of the SFB/Transregio 240 funded by the German Research Council (Deutsche Forschungsgemeinschaft, DFG). T.C. was supported by the ERC (END-HOMRET). H.N. is supported by the Clinician Scientist Program of the DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel. H.F.L., J.E. and H.N. are supported by the ERA (PerMed JTC2020).

Research Areas and Centers

Centers: Cardiological Center Luebeck (UHZL)

DFG Research Classification Scheme

2.22-12 Cardiology, Angiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-021-23499-w

Cite this

Nording, H., Baron, L., Haberthür, D., Emschermann, F., Mezger, M., Sauter, M., Sauter, R., Patzelt, J., Knoepp, K., Nording, A., Meusel, M., Meyer-Saraei, R., Hlushchuk, R., Sedding, D., Borst, O., Eitel, I., Karsten, C. M., Feil, R., Pichler, B., ... Langer, H. F. (2021). The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets. Nature Communications, 12(1), 3352. Article 3352. https://doi.org/10.1038/s41467-021-23499-w

@article{6af1ccad7eb745b4b199cacef3d40c09,

title = "The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets",

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.",

author = "Henry Nording and Lasse Baron and David Haberth{\"u}r and Frederic Emschermann and Matthias Mezger and Manuela Sauter and Reinhard Sauter and Johannes Patzelt and Kai Knoepp and Anne Nording and Moritz Meusel and Roza Meyer-Saraei and Ruslan Hlushchuk and Daniel Sedding and Oliver Borst and Ingo Eitel and Karsten, \{Christian M.\} and Robert Feil and Bernd Pichler and Jeanette Erdmann and Admar Verschoor and Emmanouil Chavakis and Triantafyllos Chavakis and \{von Hundelshausen\}, Philipp and J{\"o}rg K{\"o}hl and Meinrad Gawaz and Langer, \{Harald F.\}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-23499-w",

language = "English",

volume = "12",

pages = "3352",

journal = "Nature Communications",

issn = "1751-8628",

publisher = "John Wiley \& Sons Inc.",

number = "1",

}

Nording, H, Baron, L, Haberthür, D, Emschermann, F, Mezger, M, Sauter, M, Sauter, R, Patzelt, J, Knoepp, K, Nording, A, Meusel, M, Meyer-Saraei, R, Hlushchuk, R, Sedding, D, Borst, O, Eitel, I, Karsten, CM, Feil, R, Pichler, B, Erdmann, J, Verschoor, A, Chavakis, E, Chavakis, T, von Hundelshausen, P, Köhl, J, Gawaz, M & Langer, HF 2021, 'The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets', Nature Communications, vol. 12, no. 1, 3352, pp. 3352. https://doi.org/10.1038/s41467-021-23499-w

TY - JOUR

T1 - The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets

AU - Nording, Henry

AU - Baron, Lasse

AU - Haberthür, David

AU - Emschermann, Frederic

AU - Mezger, Matthias

AU - Sauter, Manuela

AU - Sauter, Reinhard

AU - Patzelt, Johannes

AU - Knoepp, Kai

AU - Nording, Anne

AU - Meusel, Moritz

AU - Meyer-Saraei, Roza

AU - Hlushchuk, Ruslan

AU - Sedding, Daniel

AU - Borst, Oliver

AU - Eitel, Ingo

AU - Karsten, Christian M.

AU - Feil, Robert

AU - Pichler, Bernd

AU - Erdmann, Jeanette

AU - Verschoor, Admar

AU - Chavakis, Emmanouil

AU - Chavakis, Triantafyllos

AU - von Hundelshausen, Philipp

AU - Köhl, Jörg

AU - Gawaz, Meinrad

AU - Langer, Harald F.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85107547325

UR - https://www.mendeley.com/catalogue/c37af674-9a1e-3795-8b1f-6b6fdd5d2161/

U2 - 10.1038/s41467-021-23499-w

DO - 10.1038/s41467-021-23499-w

M3 - Journal articles

C2 - 34099640

AN - SCOPUS:85107547325

SN - 1751-8628

VL - 12

SP - 3352

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3352

ER -

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

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this