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

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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.