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

The effects of raloxifene and 17α-ethinyl estradiol (EE 2 ) on intimal thickening in response to balloon injury were tested in male and ovariectomized female rats. In male rats, oral raloxifene and EE 2 , administered either by gavage or in the diet, inhibited arterial intimal thickening in response to balloon injury to a maximum of ∼60 and 50%, respectively. The effect of oral raloxifene to decrease cholesterol was observed at doses (≥3 mg/kg/day) higher than those required to inhibit intimal thickening (≥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 EE 2 . Direct adventitial delivery of raloxifene (0.03 mg/kg/day) and EE 2 (0.001 mg/kg/day) to the vascular wall inhibited intimal thickening by 63 and 53%, respectively. In ovariectomized female rats, oral raloxifene (0.01-3.0 mg/kg/day) and EE 2 (0.08 mg/kg/day) inhibited intimal thickening to a maximum of 32 and 60%, respectively. Together, these data suggest that raloxifene and EE 2 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.