Abstract
BackgroundThe placental syncytiotrophoblast is the major source of maternal plasma corticotropin-releasing hormone (CRH) in the second half of pregnancy. Placental CRH exerts multiple functions in the maternal organism: It induces the adrenal secretion of cortisol via the stimulation of adrenocorticotropic hormone, regulates the timing of birth via its actions in the myometrium and inhibits the invasion of extravillous trophoblast cells in vitro. However, the auto- and paracrine actions of CRH on the syncytiotrophoblast itself are unknown. Intrauterine growth restriction (IUGR) is accompanied by an increase in placental CRH, which could be of pathophysiological relevance for the dysregulation in syncytialisation seen in IUGR placentas.MethodsWe aimed to determine the effect of CRH on isolated primary trophoblastic cells in vitro. After CRH stimulation the trophoblast syncytialisation rate was monitored via syncytin-1 gene expression and beta-hCG (beta-human chorionic gonadotropine) ELISA in culture supernatant. The expression of the IUGR marker genes leptin and 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) was measured continuously over a period of 72 h. We hypothesized that CRH might attenuate syncytialisation, induce leptin, and reduce 11beta-HSD2 expression in primary villous trophoblasts, which are known features of IUGR.ResultsCRH did not influence the differentiation of isolated trophoblasts into functional syncytium as determined by beta-hCG secretion, albeit inducing syncytin-1 expression. Following syncytialisation, CRH treatment significantly increased leptin and 11beta-HSD2 expression, as well as leptin secretion into culture supernatant after 48 h.ConclusionThe relevance of CRH for placental physiology is underlined by the present in vitro study. The induction of leptin and 11beta-HSD2 in the syncytiotrophoblast by CRH might promote fetal nutrient supply and placental corticosteroid metabolism in the phase before labour induction.
Highlights
The placental syncytiotrophoblast is the major source of maternal plasma corticotropin-releasing hormone (CRH) in the second half of pregnancy
We found that CRH induced leptin and 11βHSD2 expression, without affecting syncytialisation of trophoblastic cells
Our pilot study showed no difference of repetitive stimulation vs. single application of CRH to the cell culture, with significant changes in gene expression between vehicle and CHR-treated groups starting with 48 h (1.0 and 2.0 μg/ml CRH) for the analysed genes. 72 h were chosen as the maximum observational period, because our previous experiments have shown that cytotrophoblast viablitiy steadily decreases afterwards
Summary
The placental syncytiotrophoblast is the major source of maternal plasma corticotropin-releasing hormone (CRH) in the second half of pregnancy. Placental CRH exerts multiple functions in the maternal organism: It induces the adrenal secretion of cortisol via the stimulation of adrenocorticotropic hormone, regulates the timing of birth via its actions in the myometrium and inhibits the invasion of extravillous trophoblast cells in vitro. There is growing evidence that a dysregulation of spiral artery invasion by EVT in the first trimester is a process contributing to the vascular resistance observed in the pregnancy complications preeclampsia and intrauterine growth restriction (IUGR) in late pregnancy [21,22] In line with this finding, we and others have previously shown that placental CRH expression and CRH in maternal plasma are significantly elevated in IUGR [23,24,25,26]. IUGR is further pathophysiologically characterized by a reduction in trophoblastic syncytialisation rate [27], increased leptin [28] and reduced 11β-HSD2 [29] expression
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