Functional interactions between the activated coagulation factor-X (FXa) and sphingosine-1-phosphate in vascular smooth muscle cells

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The activated coagulation factor-Xa (FXa) plays a key role not only in blood coagulation, but also acts via G-protein coupled receptors as a mitogen and cytokine for vascular smooth muscle cells (SMC). These cellular actions of FXa may contribute to proinflammatory responses in the vessel wall and facilitate the progression of vascular diseases such as atherosclerosis and restenosis after vascular injury. We have shown that FXa induces expression of sphingosine kinase-1 (SPHK1), the enzyme which generates the signaling lipid sphingosine-1-phosphate (S1P), in human vascular SMC. The resulting increased synthesis of S1P regulated important cellular effects of FXa such as proliferation and migration of SMC and endothelial permeability. Novel data suggest that S1P also regulates the expression of the cellular receptors for FXa and thrombin as well as the generation of thrombin and thus may affect thrombus formation. The consequences of these mutual FXa-S1P interactions shall be investigated in three selected aspects: (i) characterizing the role of S1P for the regulation of the cellular receptors for FXa and thrombin; (ii) determining the involvement of S1P in the initiation of thrombin generation and clot formation; (iii) investigating the potential effect of novel coagulation inhibitors for S1P synthesis and the impact on atherosclerotic plaques progression in vivo. It is expected to gain novel insights into the mechanisms of the development of atherosclerosis and thrombus formation for the benefit of potential new therapeutic strategies.