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 ³H] 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.