Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5 |
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The platelets C5a receptor 1 (C5aR1, CD88) is a promising target for modulating vessel growth in response to ischemia | ||
H. Nording1, L. Baron1, A. Lübken2, R. Steubing3, Y. Sun2, M. Sauter2, M. Meusel1, T. Geisler4, D. Dürschmied5, C. Kleinschnitz3, H. Langer1 | ||
1Medizinische Klinik II / Kardiologie, Angiologie, Intensivmedizin, Universitätsklinikum Schleswig-Holstein, Lübeck; 2Kardioimmunologie, Universitätsklinikum Schleswig-Holstein, Lübeck; 3Klinik für Neurologie, Universitätsklinikum Essen, Essen; 4Innere Medizin III, Kardiologie und Kreislauferkrankungen, Universitätsklinikum Tübingen, Tübingen; 5I. Medizinische Klinik, Universitätsklinikum Mannheim, Mannheim; | ||
In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly characterized. 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 coronary artery and found a correlation between activated GPIIbIIIa and C5aR1. In peripheral artery disease patients, C5aR1 expression on platelets was stronger in patients who lacked PAD symptoms despite high-grade stenosis of the low extremity arteries compared to symptomatic patients. Therefore, we used genetic mouse models to characterize its significance for ischemia and growth factor-driven revascularization as well as ischemic stroke and also developmental angiogenesis. 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 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. Finally, we applied the C5aR1 inhibitor PMX-205 in vivo in the hindlimb ischemia model. This drug, which is also tested in phase II studies in humans, induced a phenotype of improved revascularization in mice. We identified a novel mechanism for inhibition of neovascularization via CXCL4 secretion induced by platelet C5aR1, which displayed significance in a human population and provides a druggable target to modulate vessel growth induced by ischemia. |
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https://dgk.org/kongress_programme/jt2022/aP1946.html |