Genome and hormones: Gender differences in physiology - Selected contribution: Estrogen receptor-alpha gene transfer inhibits proliferation and NF-kappa B activation in VSM cells from female rats

Epidemiological studies have demonstrated that hormone replacement therapy with estrogen (E-2) or E-2 plus progesterone in postmenopausal women decrea ses the age-associated risk of cardiovascular disease by 30-50%. Treatment of vascular smooth muscle (VSM) cells with physiological concentrations of E-2 has been shown to inhibit growth factor-stimulated cell proliferation. In this study, we tested the hypothesis that E-2 inhibits the age-associate d increase in VSM cell proliferation by inhibiting nuclear factor (NF)-kapp aB pathway. We investigated the effects of E2 treatment and adenovirus-medi ated estrogen receptor (ER)-alpha gene transfer on cell proliferation and N F-kappaB activation using VSM cells cultured from 3-mo-old and 24-mo-old Fi scher 344 female rats. Our results demonstrate that VSM cell proliferation was significantly increased (P< 0.05) in aged compared with young adult fem ale rats. Treatment of VSM cells with physiological concentrations of E-2 i nhibited VSM cell proliferation, and this inhibition was significantly grea ter (P< 0.05) in cells from aged female rats compared with young adults. Th e inhibitory effects of E-2 on cell proliferation in aged female rats were significantly potentiated by overexpression of the human ER-alpha gene into VSM cells. Constitutive and interleukin (IL)-1 beta -stimulated NF-kappaB activation was significantly greater (P< 0.05) in VSM cells from aged compa red with young female rats. E-2 treatment of VSM cells from aged female rat s inhibited both constitutive and IL-1<beta>-stimulated NF-kappaB activatio n. ER-alpha gene transfer into VSM cells from aged female rats further augm ented the inhibitory effects of E-2. In conclusion, our data demonstrate th at constitutive and IL-1 beta -stimulated NF-kappaB activation is increased in VSM cells from aged female rats due to loss of E-2 and this can be rest ored back to normal levels by ER-alpha gene transfer and E-2 treatment. In addition, increased NF-kappaB signaling may be responsible for increased in cidence of cardiovascular disease in postmenopausal females.