title: Inhibition of placental 11beta-hydroxysteroid dehydrogenase type 2 by catecholamines via alpha-adrenergic signaling.
abstract: The placenta expresses high levels of 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) that converts cortisol into inactive 11-keto metabolites and effectively protects the developing fetus from maternal cortisol during pregnancy. Impairment of this glucocorticoid barrier has adverse effects on fetal outcomes. A similar spectrum of adverse fetal effects is induced by antenatal stress during pregnancy. To examine the hypothesis that physiological stress may regulate placental 11betaHSD2 gene expression, we examined the effects of the catecholamines norepinephrine (NE) and epinephrine (E) on 11betaHSD2 expression in human trophoblastic cells. With the use of Northern blotting and semiquantitative RT-PCR, we determined that NE and E rapidly downregulate 11betaHSD2 steady-state mRNA levels in early- and late-gestation human trophoblasts and BeWo trophoblastic cells. Experiments using different adrenoceptor subtype-selective agonists and antagonists demonstrated that this catecholamine suppression of 11betaHSD2 mRNA expression is mediated via both alpha(1)- and alpha(2)-adrenoceptors and is independent of beta-adrenergic stimulation. To examine transcriptional regulation, BeWo cells were transiently transfected with a reporter construct in which an 11betaHSD2 human promoter sequence was inserted upstream of the luciferase gene. Treatment with 10(-7) M NE decreased luciferase activity by ~60% (n = 3, P < 0.01). These results suggest the NE/E-mediated decrease in placental 11betaHSD2 gene expression is an instance of alpha-adrenoceptor-specific rapid transcriptional inhibition of an adrenergic target gene. This molecular mechanism may be involved in the deleterious effects of antenatal physiological stress on fetoplacental growth and development.
authors.affiliation: Department of Pediatrics, Brown Medical School, Providence, Rhode Island 02905-2499, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sarkar
authors.forename: S W
authors.initials: SW
authors.lastname: Tsai
authors.forename: T T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: M
authors.initials: M
authors.lastname: Plevyak
authors.forename: J F
authors.initials: JF
authors.lastname: Padbury
authors.forename: L P
authors.initials: LP
authors.lastname: Rubin
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D002585:Cesarean Section; D002824:Chorionic Villi / Q000201:enzymology; D017931:DNA Primers; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005865:Gestational Age; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics*; D009638:Norepinephrine / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011412:Propanolamines / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D014327:Trophoblasts / Q000201:enzymology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D001381:Azepines; D017931:DNA Primers; D011412:Propanolamines; D011942:Receptors, Adrenergic, alpha; D011994:Recombinant Proteins; C026777:ICI 118551; C015603:azepexole; D006913:Hydroxysteroid Dehydrogenases; D009638:Norepinephrine