Dihydrotestosterone and estradiol-17β mutually neutralize their inhibitory effects on human vascular smooth muscle cell growth in vitro

We reported previously that high concentrations of either estradiol-17β (E2) or dihydrotestosterone (DHT) inhibit growth of human cultured vascular smooth muscle cells (VSMC), mediated by cell membrane receptors and MAP-kinase–kinase activity (MEK). We now tested whether the presence of the opposite gender's dominant sex hormone modifies these effects. We incubated VSMC with various concentrations of E2 and DHT or protein bound hormones (E2–BSA or T–BSA), alone or in various combinations. High concentration of E2 or E2–BSA inhibited VSMC growth and stimulated MEK. In the presence of 3 nM DHT, high concentration of E2 no longer inhibited 3[H] thymidine incorporation or increased MEK. Moreover, when high DHT concentration (300 nM) was added to VSMC exposed to high E2, VSMC growth actually increased without change in MEK. DHT at 300 nM suppressed VSMC growth and increased MEK while 0.3 nM E2 had only marginal effect on this interaction, and 30 nM E2 reversed the inhibitory effect of DHT on cell growth. The inhibitory effects of both E2 and DHT on VSMC cell growth and the stimulation of MEK was apparently mediated by cell membrane receptors, as it persisted when bovine serum albumin (BSA)-bound hormones were used. Further, inhibition of VSMC growth induced by E2–BSA was reversed in the presence of T–BSA and vice versa. These results suggest that while female and male sex hormones affect VSMC growth similarly, they interfere in a dose-, hormone- and MEK-dependent manner with each other's effect.