Rivaroxaban, a factor Xa inhibitor, improves neovascularization in the ischemic hindlimb of streptozotocin-induced diabetic mice

BACKGROUND: Factor Xa inhibitor is used for preventing venous thromboembolism (VTE) in adult patients receiving orthopedic operation. However, the role of factor Xa inhibitor, rivaroxaban, in angiogenesis is still unknown. METHODS AND RESULTS: Streptozotocin (STZ)–induced diabetic mice with model of hind-limb ischemia, were divided into non-diabetic control, diabetic control, and low- and high-dose rivaroxaban treatment groups, in order to evaluate the effect of rivaroxaban in angiogenesis. Doppler perfusion imaging showed that blood flow recovery was significantly increased, and more capillary density occurred in the rivaroxaban treatment group. In vitro studies, human endothelial progenitor cells (EPCs) treated with rivaroxaban had significant functional improvement in migration and senescence under hyperglycemic conditions. Rivaroxaban also increased endothelial nitric oxide synthase (eNOS) as well as vascular endothelial growth factor (VEGF) expressions in hyperglycemia-stimulated EPCs. CONCLUSIONS: Rivaroxaban promoted vessel formation in diabetic mice and improved endothelial progenitor cell function under hyperglycemic conditions. These effects may be associated with enhancement of expression of eNOS and VEGF.