Abstract 5541: Erythropoietin Receptor Signaling Exacerbates Neointimal Hyperplasia in the Rat Carotid Artery After Balloon Injury
Treatment with erythropoietin (EPO) was reported to accelerate reendothelialization, accompanying endothelial progenitor cell (EPC) induction, to result in suppression of neointimal hyperplasia in the carotid artery after balloon injury. We injured the right carotid artery of male SD rats (200 to 250 g) with an oversized balloon. Treatment with recombinant human EPO (1000 IU/kg/day) or asialoerythropoietin (AEPO, 1000 IU/kg/day), a nonerythrogenic derivative of EPO, was started at 1 week after injury when neointimal proliferates and continued for 3 days. The rats were examined 2 weeks after the surgery. The hemoglobin level was significantly increased in the EPO-treated rats but was unchanged in the saline control and AEPO-treated groups. FACS analysis revealed significantly increased circulating EPCs in the EPO-treated group but not in the AEPO-treated group. Reendothelialization was accelerated in both EPO- and AEPO-treated groups. However, the area of neointima was significantly greater in both treatment groups compared with the control group and accordingly the area of neointimal to medial area ratio (%) was significantly greater in the EPO- (150+/−26%) and AEPO-treated (157+/−15%) groups compared with the control group (132+/−7%). Alpha-smooth muscle actin-positive cell population was also greater in both treatment groups. The incidence of proliferating cells labeled with Ki-67 antigen was significantly greater not only in the endothelium but also in the neointima of the EPO- and AEPO-treated groups compared with the control group. In conclusion, EPO receptor signaling can proliferate not only endothelial cells but also intimal smooth muscle-like cells independently of EPC induction, which might have aggravated neointimal hyperplasia when EPO receptor was stimulated at the phase of intimal proliferation after injury. These findings caution an easy use of EPO in patients after vascular intervention.