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

活化的凝血因子Xa（FXa）不仅在血液凝固中起关键作用，而且通过G蛋白偶联受体作为血管平滑肌细胞（SMC）的促分裂原和细胞因子起作用。FXa的这些细胞作用可能有助于血管壁中的促炎反应，并促进血管疾病如动脉粥样硬化和血管损伤后再狭窄的进展。我们已经表明，FXa诱导鞘氨醇激酶-1（SPHK 1）的表达，该酶在人血管SMC中产生信号脂质鞘氨醇-1-磷酸（S1 P）。由此产生的S1 P合成增加调节FXa的重要细胞效应，如SMC的增殖和迁移以及内皮通透性。新的数据表明，S1 P还调节FXa和凝血酶的细胞受体的表达以及凝血酶的产生，从而可能影响血栓形成。这些相互的FXa-S1 P相互作用的结果应在三个选定的方面进行研究：（i）表征S1 P对FXa和凝血酶的细胞受体的调节作用;（ii）确定S1 P参与凝血酶产生和凝块形成的起始;（iii）研究新型凝血抑制剂对S1 P合成的潜在作用和对体内动脉粥样硬化斑块进展的影响。它有望获得新的见解的发展动脉粥样硬化和血栓形成的机制，为潜在的新的治疗策略的好处。

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.