Role of platelet SIP and SDF-la for the inflammatory and proliferative responses following arterial injury and during atherogenesis

在动脉粥样硬化和动脉粥样硬化血栓形成过程中，炎症和增殖反应对于有益的“血管愈合”和有害的“血管重塑”至关重要。活化的血小板被招募到受损/病变的血管壁，释放强大的趋化因子并产生旁分泌介质，这可能是控制成熟的白细胞和未成熟的祖细胞(内皮祖细胞、造血干/祖细胞)向动脉血管壁运输所必需的。特别是，我们和其他人最近发现，血小板可以释放CXC趋化因子SDF-1a和磷酸化的鞘氨醇代谢物1-磷酸鞘氨醇(Sphingosine 1-POP)。本研究的目的是明确研究在血管损伤后和动脉粥样硬化过程中，血小板表面蛋白和SDF-1a在不同的成熟白细胞和未成熟祖细胞群体向血管内膜募集中的作用。我们的兴趣将进一步集中在参与血小板黏附和激活过程中分泌SIP和SDF-1a的信号级联。利用突变的小鼠模型，我们最终将评估血小板表面蛋白和SDF-1a在与动脉血栓形成和动脉粥样硬化相关的增殖反应中的作用。上面概述的项目将有助于扩大我们目前对促进血管炎症和重塑的细胞过程的了解。

During atherosclerosis and atherothrombosis, inflammatory and proliferative responses are critically for beneficial "vascular healing" and for detrimental "vascular remodeling". Activated platelets, which are recruited to the damaged/diseased vessel wall, release potent chemokines and generate paracrine mediators that might be essential to control the trafficking of mature leukocytes and immature progenitor cells (endothelial progenitor cells, hematopoietic stem/progenitor cells) to the arterial vessel wall. In particular, platelets have recently been shown by us and others to release the CXC chemokine SDF-la and the phosphorylated sphingolipid metabolite sphingosine 1-phosphate (SIP). The aim of our present project is to specifically address the role of platelet SIP and SDF-la for the recruitment of distinct mature leukocytes and immature progenitor cell populations to the vascular intima following vessel injury and during atherosclerosis. Our interest will further focus on the signaling cascades that are involved in the secretion of SIP and SDF-la during platelet adhesion and activation. Using mutant mouse models, we will finally evaluate the contribution of platelet SIP and SDF-la to the proliferative responses associated with arterial thrombosis and atherosclerosis. The project outlined above will help to enlarge our current knowledge of the cellular processes that contribute to vascular inflammation and remodeling.