Down-Regulation of Neutral Sphingomyelinase in Androgen-Dependent Smooth Muscle

BackgroundDuring puberty, proliferation of guinea pig seminal vesicle smooth muscle (SVM) is mediated by androgen-induced basal release of norepinephrine (NE), signaling through the post-junctional α1-adrenoceptor. In the adult, the SVM is terminally differentiated, such that cell number is androgen resistant. Sphingomyelinase activation generates second messenger ceramides, which in vascular smooth muscle have been reported to counter the α1-adrenoceptor-mediated contractile response and activate apoptosis. Accordingly, we hypothesized that SVM sphingomyelinase down-regulation by androgen may facilitate NE-induced proliferation and subsequent transition to the terminally differentiated state of the adult.Materials and methodsPre-pubertal and adult guinea pigs were orchiectomized and treated ± dihydrotestosterone (DHT). SVM was harvested free of epithelium, frozen, and stored for enzymatic analyses. Using radioactive sphingomyelin substrate, optimized reaction conditions for both neutral and acidic sphingomyelinase were established and used to assay the enzymes.ResultsAlthough acidic sphingomyelinase was stimulated by androgen in both the proliferative and amitotic phases of smooth muscle development, neutral sphingomyelinase was irreversibly reduced 35% at the time of DHT-induced proliferation.ConclusionsDecreased concentrations of a second messenger ceramide attenuate apoptosis and increase sensitivity to α1-adrenoceptor-mediated mitogenic signaling. Therefore, DHT-dependent suppression of neutral sphingomyelinase activity may reduce ceramide concentrations and facilitate NE-dependent smooth muscle growth.