Gender-related Differences in Smooth Muscle Cell Proliferation in Response to Estradiol and Dihydrotestosterone

The cardioprotective effect of estradiol (E2) is strongly supported by the reduced incidence of coronary artery disease (CAD) observed in premenopausal females versus age-matched males and in postmenopausal females on estrogen therapy. The favorable effect of estrogen on lipid profiles does not fully account for the observed cardiac benefits in females versus males. We have previously demonstrated that physiologic concentrations of E2 inhibit female pig coronary vascular smooth muscle cells (VSMC) in vitro; this may partially account for estrogenʹs favorable cardiac effects. We determined the effect of sex steroids [dihydrotestosterone (DHT) and E2] and tamoxifen (an anti-estrogen) on proliferation of coronary VSMC obtained from male pigs. VSMC were cultured in phenol red-free Medi 199 with 10% fetal calf serum. Cells obtained from mature adult male pigs were growth arrested in serum-free medi for 24 hours, and treated with effectors in 2% charcoal-stripped serum at concentrations ranging from 10−11 to 10−7 M for 24 hours. Cell proliferation was assessed by tritiated thymidine incorporation corrected for protein content. No significant effect on proliferation was observed in E2 or tamoxifen-treated cells versus vehicle controls. Proliferation was significantly increased in cells treated with DHT at 10−11 M. In conclusion, E2 did not inhibit proliferation of coronary VSMC obtained from intact male animals, in contrast to the inhibition observed previously in VSMC obtained from intact female pigs. This gender-related differential response in vitro to E2 may partially explain the reduction in CAD in estrogen-replete women compared to men. Tamoxifen had no effect on VSMC proliferation. The increased proliferation of VSMC in response to dihydrotestosterone may play role in the pathogenesis of CAD in males.