Abstract
Uncontrolled coagulation contributes to the pathophysiology of several chronic inflammatory diseases. In these conditions, senescent cells are often observed and is involved in the generation of inflammation. The coincidence of hyper-coagulation, cell senescence, and inflammation suggests the existence of a common underlying mechanism. Recent evidence indicates that activated coagulation factor X (FXa) plays a role in the processes beyond blood coagulation. This non-hematologic function entails the mediation of inflammation and tissue remodeling. We therefore tested the hypothesis that FXa induces cell senescence resulting in tissue inflammation and impaired tissue regeneration. Human umbilical vein endothelial cells were stimulated with FXa for 14 days. The proliferation of cells treated with FXa was significantly smaller, and the fraction of senescence-associated β-galactosidase-positive cells was increased as compared to the control group. RT-qPCR array revealed that FXa increased the expression of IGFBP-5, EGR-1, p53, and p16INK4a. Inhibition of FXa by a direct FXa inhibitor, rivaroxaban, or IGFBP-5 by siRNA decreased FXa-induced cell senescence, restoring cell proliferation. Moreover, in an ischemic hind limb mouse model, FXa inhibited neovascularization by endothelial progenitor cell. However, rivaroxaban significantly restored FXa-induced impaired angiogenesis. In summary, FXa induced endothelial cell senescence through IGFBP-5, resulting in impaired angiogenesis.
Highlights
In this study, we demonstrated that continuous FXa stimulation decreased EC proliferation, up-regulating the senescence marker such as p53, p16INK4a, and senescence-associated β-galactosidase (SA-βgal)-positive cells, through up-regulation of insulin-like growth factor binding protein 5 (IGFBP-5) and early growth response 1 (EGR-1)
This study aimed to evaluate the response of EC to chronic FXa stimulation, focusing on cellular senescence, which is often seen in tissues affected by chronic inflammatory diseases and appears to contribute to low grade inflammation through SASP9
Our data consistently indicated that FXa induced IGFBP-5 expression through both protease-activated receptor 1 (PAR1) and PAR2 in vitro
Summary
We demonstrated that continuous FXa stimulation decreased EC proliferation, up-regulating the senescence marker such as p53, p16INK4a, and senescence-associated β-galactosidase (SA-βgal)-positive cells, through up-regulation of insulin-like growth factor binding protein 5 (IGFBP-5) and early growth response 1 (EGR-1). The present study demonstrated that FXa impaired angiogenesis via senescence of endothelial progenitor cell (EPC), while the direct FXa inhibitor, rivaroxaban, attenuated the impaired the angiogenic properties induced by FXa in mouse ischemic hind limb model. These data indicated that FXa induced EC and EPC senescence, leading to impaired angiogenesis
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