Activated Factor X Induces Endothelial Cell Senescence Through IGFBP-5

Area of Science:

• Biochemistry
• Cell Biology
• Pathophysiology

Background:

• Uncontrolled coagulation is implicated in chronic inflammatory diseases.
• Cellular senescence and inflammation often coexist in these conditions.
• Coagulation factor Xa (FXa) has non-hemostatic roles in inflammation and tissue remodeling.

Purpose of the Study:

• To investigate if FXa induces cell senescence, leading to tissue inflammation and impaired regeneration.
• To explore the molecular mechanisms underlying FXa-mediated senescence and inflammation.

Main Methods:

• Human umbilical vein endothelial cells were treated with FXa for 14 days.
• Senescence markers (β-galactosidase, p53, p16INK4a) and gene expression (IGFBP-5, EGR-1) were analyzed.
• FXa inhibition (rivaroxaban) and IGFBP-5 knockdown (siRNA) effects were assessed.
• An ischemic hind limb mouse model was used to evaluate FXa's impact on angiogenesis.

Main Results:

• FXa treatment significantly reduced endothelial cell proliferation and increased senescence.
• FXa upregulated key senescence-related genes, including IGFBP-5 and p53.
• Rivaroxaban and IGFBP-5 inhibition reversed FXa-induced senescence and restored proliferation.
• FXa impaired neovascularization in a mouse model, an effect reversed by rivaroxaban.

Conclusions:

• FXa induces endothelial cell senescence, mediated by IGFBP-5.
• This senescence contributes to impaired angiogenesis and tissue inflammation.
• Targeting FXa may offer therapeutic potential for inflammatory diseases involving coagulation and senescence.