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.
Highlights
Platelets contribute to the regulation of tissue neovascularization, the specific factors underlying this function are unknown
While it has been described that platelets contain proangiogenic and antiangiogenic factors[27], very little information exists regarding their regulatory function of hypoxia-driven revascularization and on how the release of these paracrine mediators is regulated
100%. *p < 0.05. n In order to uncover the signaling downstream of C5a receptor 1 (C5aR1) leading to CXCL4 secretion, lysates of WT platelets were generated after vehicle control or C5a stimulation and samples were probed at equal protein concentrations for phospho-proteins as well as non-phosphorylated controls
Summary
Platelets contribute to the regulation of tissue neovascularization, the specific factors underlying this function are unknown. 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. Platelets play a decisive role in diseases that are featured by thrombus formation, and targeting platelet-associated functions is an established therapeutic principle for treating these diseases[14,15] Beyond their classical function in blood hemostasis, platelets contribute to inflammation[16], immunomodulation[17,18], and atherosclerosis[19]. Platelet αgranules contain proangiogenic vascular endothelial growth factor (VEGF) and antiangiogenic CXC chemokine ligand 4 (CXCL4, PF425–27). We addressed the crosstalk between the complement system and platelets in the context of ischemia-induced revascularization in vivo and find that C5a receptor 1 (C5aR1) expressed on platelets regulates the angiogenesis-related functions of platelets
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