Raloxifene and estrogen inhibit neointimal thickening after balloon injury in the carotid artery of male and ovariectomized female rats

The effects of raloxifene and 17 alpha-ethinyl estradiol (EE2) on intimal thickening in response to balloon injury were tested in male and ovariectomized female rats. In male rats, oral raloxifene and EE2, administered either by gavage or in the diet, inhibited arterial intimal thickening in response to balloon injury to a maximum of similar to 60 and 50%, respectively. The effect of oral raloxifene to decrease cholesterol was observed at doses (greater than or equal to 3 mg/kg/day) higher than those required to inhibit intimal thickening (greater than or equal to 0.03 mg/kg/day). Coadministration of the estrogen receptor antagonist, ICI 182,780 (5 mg/kg/day, s.c.), blocked the inhibition of balloon injury by raloxifene and EE2. Direct adventitial delivery of raloxifene (0.03 mg/kg/day) and EE2 (0.001 mg/kg/day) to the vascular wall inhibited intimal thickening by 63 and 53%, respectively. In ovariectomized fe male rats, oral raloxifene (0.01-3.0 mg/kg/day) and EE2 (0.08 mg/kg/day) inhibited intimal thickening to a maximum of 32 and 60%, respectively. Together, these data suggest that raloxifene and EE2 inhibit balloon arterial injury in the rat through direct effects on the vascular wall that involve the estrogen receptor and are at least partially independent of serum cholesterol.