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

Abstract

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.

• Authors: Henry Nording, Lasse Baron, Manuela Sauter, Antje Lübken, Elias Rawish, Rebecca Szepanowski, Jacob von Esebeck, Ying Sun, Hossein Emami, Moritz Meusel, Roza Saraei, Nancy Schanze, Sivahari Prasad Gorantla, Nikolas von Bubnoff, Tobias Geisler, Philipp von Hundelshausen, Konstantinos Stellos, Jens Marquardt, Christian D Sadik, Jörg Köhl, Daniel Duerschmied, Christoph Kleinschnitz, Harald F Langer
• Journal: Blood advances (Blood Adv) Vol. 7 Issue 21 Pg. 6411-6427 (11 14 2023) ISSN: 2473-9537 [Electronic] United States
• PMID: 37257194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 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.

Chemical References

• Intercellular Signaling Peptides and Proteins
• Anaphylatoxins
• Receptor, Anaphylatoxin C5a

Topics

• Humans
• Mice
• Animals
• Intercellular Signaling Peptides and Proteins
• Anaphylatoxins
• Ischemia (etiology)
• Receptor, Anaphylatoxin C5a