Ursolic acid induces allograft inflammatory factor-1 expression via a nitric oxide-related mechanism and increases neovascularization

Ursolic acid (UA), a triterpenoid compound found in plants, is used in the human diet and in medicinal herbs and possesses a wide range of biological benefits including antioxidative, anti-inflammatory, and anticarcinogenic effects. Endothelial expression of allograft inflammatory factor-1 (AIF-1) mediates vasculogenesis, and nitric oxide (NO) produced by endothelial NO (eNOS) represents a mechanism of vascular protection. It is unclear whether UA affects the neovascularization mediated by AIF-1 and eNOS expression. This study investigated the effects and mechanisms of UA on angiogenesis in vivo in hind limb ischemic animal models and in vitro in human coronary artery endothelial cells (HCECs). This study explored the impact of UA on endothelial cell (EC) activities in vitro in HCECs, vascular neovasculogenesis in vivo in a mouse hind limb ischemia model, and the possible role of AIF-1 in vasculogenesis. The results demonstrate that UA enhances collateral blood flow recovery through induction of neovascularization in a hind limb ischemia mouse model. In vitro data showed that UA increases tube formation and migration capacities in human endothelial cells, and exposing HCECs to UA increased AIF-1 expression through a NO-related mechanism. Moreover, UA administration increased capillary density and eNOS and AIF-1 expression in ischemic muscle. These findings suggest that UA may be a potential therapeutic agent in the induction of neovascularization and provide a novel mechanistic insight into the potential effects of UA on ischemic vascular diseases.