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Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor–modulating factors

In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) expressed on platelets as a potent regulator of ischemia-driv...

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Autores principales: Nording, Henry, Baron, Lasse, Sauter, Manuela, Lübken, Antje, Rawish, Elias, Szepanowski, Rebecca, von Esebeck, Jacob, Sun, Ying, Emami, Hossein, Meusel, Moritz, Saraei, Roza, Schanze, Nancy, Gorantla, Sivahari Prasad, von Bubnoff, Nikolas, Geisler, Tobias, von Hundelshausen, Philipp, Stellos, Konstantinos, Marquardt, Jens, Sadik, Christian D., Köhl, Jörg, Duerschmied, Daniel, Kleinschnitz, Christoph, Langer, Harald F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society of Hematology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598500/
https://www.ncbi.nlm.nih.gov/pubmed/37257194
http://dx.doi.org/10.1182/bloodadvances.2021006891
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author Nording, Henry
Baron, Lasse
Sauter, Manuela
Lübken, Antje
Rawish, Elias
Szepanowski, Rebecca
von Esebeck, Jacob
Sun, Ying
Emami, Hossein
Meusel, Moritz
Saraei, Roza
Schanze, Nancy
Gorantla, Sivahari Prasad
von Bubnoff, Nikolas
Geisler, Tobias
von Hundelshausen, Philipp
Stellos, Konstantinos
Marquardt, Jens
Sadik, Christian D.
Köhl, Jörg
Duerschmied, Daniel
Kleinschnitz, Christoph
Langer, Harald F.
author_facet Nording, Henry
Baron, Lasse
Sauter, Manuela
Lübken, Antje
Rawish, Elias
Szepanowski, Rebecca
von Esebeck, Jacob
Sun, Ying
Emami, Hossein
Meusel, Moritz
Saraei, Roza
Schanze, Nancy
Gorantla, Sivahari Prasad
von Bubnoff, Nikolas
Geisler, Tobias
von Hundelshausen, Philipp
Stellos, Konstantinos
Marquardt, Jens
Sadik, Christian D.
Köhl, Jörg
Duerschmied, Daniel
Kleinschnitz, Christoph
Langer, Harald F.
author_sort Nording, Henry
collection PubMed
description In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) expressed on platelets as a potent regulator of ischemia-driven revascularization. We assessed the relevance of the anaphylatoxin receptor C5aR1 on platelets in patients with coronary artery disease as well as those with peripheral artery disease and used genetic mouse models to characterize its significance for ischemia and growth factor–driven revascularization. The presence of C5aR1-expressing platelets was increased in the hindlimb ischemia model. Ischemia-driven angiogenesis was significantly improved in C5aR1(−/−) mice but not in C5(−/−) mice, suggesting a specific role of C5aR1. Experiments using the supernatant of C5a-stimulated platelets suggested a paracrine mechanism of angiogenesis inhibition by platelets by means of antiangiogenic CXC chemokine ligand 4 (CXCL4, PF4). Lineage-specific C5aR1 deletion verified that the secretion of CXCL4 depends on C5aR1 ligation on platelets. Using C5aR1(−/−)CXCL4(−/−) mice, we observed no additional effect in the revascularization response, underscoring a strong dependence of CXCL4 secretion on the C5a-C5aR1-axis. We identified a novel mechanism for inhibition of neovascularization via platelet C5aR1, which was mediated by the release of antiangiogenic CXCL4.
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spelling pubmed-105985002023-10-26 Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor–modulating factors Nording, Henry Baron, Lasse Sauter, Manuela Lübken, Antje Rawish, Elias Szepanowski, Rebecca von Esebeck, Jacob Sun, Ying Emami, Hossein Meusel, Moritz Saraei, Roza Schanze, Nancy Gorantla, Sivahari Prasad von Bubnoff, Nikolas Geisler, Tobias von Hundelshausen, Philipp Stellos, Konstantinos Marquardt, Jens Sadik, Christian D. Köhl, Jörg Duerschmied, Daniel Kleinschnitz, Christoph Langer, Harald F. Blood Adv Vascular Biology In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) expressed on platelets as a potent regulator of ischemia-driven revascularization. We assessed the relevance of the anaphylatoxin receptor C5aR1 on platelets in patients with coronary artery disease as well as those with peripheral artery disease and used genetic mouse models to characterize its significance for ischemia and growth factor–driven revascularization. The presence of C5aR1-expressing platelets was increased in the hindlimb ischemia model. Ischemia-driven angiogenesis was significantly improved in C5aR1(−/−) mice but not in C5(−/−) mice, suggesting a specific role of C5aR1. Experiments using the supernatant of C5a-stimulated platelets suggested a paracrine mechanism of angiogenesis inhibition by platelets by means of antiangiogenic CXC chemokine ligand 4 (CXCL4, PF4). Lineage-specific C5aR1 deletion verified that the secretion of CXCL4 depends on C5aR1 ligation on platelets. Using C5aR1(−/−)CXCL4(−/−) mice, we observed no additional effect in the revascularization response, underscoring a strong dependence of CXCL4 secretion on the C5a-C5aR1-axis. We identified a novel mechanism for inhibition of neovascularization via platelet C5aR1, which was mediated by the release of antiangiogenic CXCL4. The American Society of Hematology 2023-06-02 /pmc/articles/PMC10598500/ /pubmed/37257194 http://dx.doi.org/10.1182/bloodadvances.2021006891 Text en © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Vascular Biology
Nording, Henry
Baron, Lasse
Sauter, Manuela
Lübken, Antje
Rawish, Elias
Szepanowski, Rebecca
von Esebeck, Jacob
Sun, Ying
Emami, Hossein
Meusel, Moritz
Saraei, Roza
Schanze, Nancy
Gorantla, Sivahari Prasad
von Bubnoff, Nikolas
Geisler, Tobias
von Hundelshausen, Philipp
Stellos, Konstantinos
Marquardt, Jens
Sadik, Christian D.
Köhl, Jörg
Duerschmied, Daniel
Kleinschnitz, Christoph
Langer, Harald F.
Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor–modulating factors
title Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor–modulating factors
title_full Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor–modulating factors
title_fullStr Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor–modulating factors
title_full_unstemmed Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor–modulating factors
title_short Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor–modulating factors
title_sort platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor–modulating factors
topic Vascular Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598500/
https://www.ncbi.nlm.nih.gov/pubmed/37257194
http://dx.doi.org/10.1182/bloodadvances.2021006891
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