Caffeine Reduces 11β-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Trophoblast Cells through the Adenosine A2B Receptor

Maternal caffeine consumption is associated with reduced fetal growth, but the underlying molecular mechanisms are unknown. Since there is evidence that decreased placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is linked to fetal growth restriction, we hypothesized that caffeine may inhibit fetal growth partly through down regulating placental 11β-HSD2. As a first step in examining this hypothesis, we studied the effects of caffeine on placental 11β-HSD2 activity and expression using our established primary human trophoblast cells as an in vitro model system. Given that maternal serum concentrations of paraxanthine (the primary metabolite of caffeine) were greater in women who gave birth to small-for-gestational age infants than to appropriately grown infants, we also studied the effects of paraxanthine. Our main findings were: (1) both caffeine and paraxanthine decreased placental 11β-HSD2 activity, protein and mRNA in a concentration-dependent manner; (2) this inhibitory effect was mediated by the adenosine A2B receptor, since siRNA-mediated knockdown of this receptor prevented caffeine- and paraxanthine-induced inhibition of placental 11β-HSD2; and (3) forskolin (an activator of adenyl cyclase and a known stimulator of 11β-HSD2) abrogated the inhibitory effects of both caffeine and paraxanthine, which provides evidence for a functional link between exposure to caffeine and paraxanthine, decreased intracellular levels of cAMP and reduced placental 11β-HSD2. Taken together, these findings reveal that placental 11β-HSD2 is a novel molecular target through which caffeine may adversely affect fetal growth. They also uncover a previously unappreciated role for the adenosine A2B receptor signaling in regulating placental 11β-HSD2, and consequently fetal development

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The effect of puerperal uterine disease on uterine involution in cows assessed by Doppler sonography of the uterine arteries

The objective of this study was to investigate the effects of puerperal uterine disease on uterine blood flow using trans-rectal Doppler sonography. Lactating Holstein Friesian cows (n = 44) were divided into two groups based on whether they were healthy (UD−; n = 23) or had uterine disease (UD+; n = 21) defined as retained fetal membranes and/or metritis. General clinical examination, vaginoscopy, trans-rectal palpation, and trans-rectal B-Mode sonography were conducted on Days 8, 11, 18, 25 and then every 10 days until Day 65 after calving. Doppler sonography of the uterine arteries was conducted on Day 8, during diestrus after the second ovulation (Days 40–60 after calving) and during diestrus before breeding (Days 63–75 after calving). Cows with uterine disease had greater (P < 0.05) uterine size as assessed trans-rectally compared with cows of the UD group. Sonographic measurements on Day 11 after parturition revealed a greater (P < 0.05) horn diameter in cows of the UD+ than in the UD− group. Both uterine size and uterine horn diameter decreased more earlier following parturition (P < 0.05) in cows of the UD− group. Blood flow volume (BFV) was greater and pulsatility index was less on Day 8 after calving in cows of UD+ than UD− group (P < 0.05). In cows of the UD−, but not in those of the UD+ group, there was a further reduction in BFV subsequent to Day 45 after calving (P < 0.05). The results of this study show that uterine blood flow measures by trans-rectal Doppler sonography are affected by puerperal uterine disease