【Abstract】Objective To study the effect of hirudin on angiogenesis of ischemic flap in rats and its possible mechanism. 〖WTHZ〗Methods 10 SD rats were used to establish the ischemic skin flap model. Hirudin with 2 ATU was injected subcutaneously on the right side (experimental group) and normal saline was injected subcutaneously on the left side (control group). On the 3rd and 7th day after operation, the flap tissues were examined by pathology, immunohistochemistry and vascular density. On the 7th day after operation, the survival rate of flap was calculated. The expression of vascular endothelial growth factor (VEGF), thrombospondinl (TSP1), p38 MAPK and ERK1/2 phosphorylation were detected by immunoblotting.Results Pathological examination showed that the necrosis of flap tissue in the experimental group was significantly reduced and neovascularization was significantly increased compared with the control group on the 3rd and 7th day after operation. Compared with the control group, the survival rate of flap in the experimental group was significantly increased 7 days after operation (P＜001). The results of immunohistochemistry showed that the epidermis and dermis of the skin flap in the control group were obviously necrotic on the 3rd day after operation, and no blood vessels were observed because of the large area necrosis of the skin flap in the control group on the 7th day after operation, and no obvious necrosis area was found in the skin flap in the experimental group on the 3rd and 7th day after operation. The vascular density of the experimental group was significantly higher than that of the control group on the 3rd and 7th day after operation (P＜001), and that of the experimental group on the 7th day was significantly higher than that on the 3rd day after operation (P＜005). The expression level of VEGF and TSP1 in the experimental group was significantly higher than that in the control group (P＜001). Compared with the control group, the phosphorylation level of p38 MAPK in the experimental group was significantly lower and that of ERK1/2 was significantly higher (P＜005). Conclusion Hirudin can promote the neovascularization of ischemic skin flap in rats. Its mechanism may be to induce the expression of VEGF and down regulate the expression of TSP1. Its main pathway may be closely related to p38 MAPK and ERK1/2 signal pathway.