Abstract
Factor Xa (FXa) occupies a central place in coagulation cascade as a convergence point between intrinsic and extrinsic pathways. Apart from this activity, the non-hemostatic function of FXa through protease activated receptors (PARs) triggers an intracellular activation that can initiate signaling cascades regulating migration and survival of cells. However, the direct effect of FXa on angiogenesis in endothelial cells (ECs) and endothelial progenitor cells (EPCs) is largely unknown. Here, we demonstrated that FXa treatment on both ECs and EPCs significantly increases the expression of p53 protein through PAR2 (p<0.05). Activation of p53 proteins resulted in impairment of migration and tube formation of these cells. Moreover, chronic FXa stimulation on ECs and EPCs induced cell senescence assessed by Senescence-associated beta-galactosidase (SA-β-gal) staining (p<0.05). These unfavorable effect of FXa on ECs and EPCs were diminished by co-treatment with FXa inhibitor, rivaroxaban. To test whether these in vitro observation has an in vivo counterparts, chronically treated EPCs with FXa were intravenously injected immediately after femoral artery ligation in mouse ischemic hind limb model. Laser doppler image (LDI) analysis showed that EPCs enhanced the recovery of ischemic limb perfusion and this beneficial effect of EPC was significantly blunted by FXa. Additionally, the increase in capillary density by EPCs injection was inhibited by the treatment with FXa. However, treatment with rivaroxaban significantly increased ischemic limb perfusion and capillary density compared to FXa treatment group (p<0.05). In summary, these observation indicates anti-angiogenic property of FXa via p53 upregulation. FXa inhibitor, rivaroxaban, might work as anti-senescence and maintain angiogenic ability of ECs and EPCs.
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