Retinoic Acid Pathway Regulation of Vascular Endothelial Growth Factor in Ovine Amnion
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Retinoic Acid Pathway Regulation of Vascular Endothelial Growth Factor in Ovine Amnion
Reproductive Sciences 1-9 ª The Author(s) 2018 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1933719118765979 journals.sagepub.com/home/rsx
Cecilia Y. Cheung, PhD1,2, Debra F. Anderson, PhD2, Marion Rouzaire, PhD3, Loı¨c Blanchon, PhD3, Vincent Sapin, PhD3, and Robert A. Brace, PhD1,2
Abstract Vascular endothelial growth factor (VEGF) has been proposed as an important regulator of amniotic fluid absorption across the amnion into the fetal vasculature on the surface of the placenta. However, the activators of VEGF expression and action in the amnion have not been identified. Using the pregnant sheep model, we aimed to investigate the presence of the retinoic acid (RA) pathway in ovine amnion and to determine its effect on VEGF expression. Further, we explored relationships between RA receptors and VEGF and tested the hypothesis that RA modulates intramembranous absorption (IMA) through induction of amnion VEGF in sheep fetuses subjected to altered IMA rates. Our study showed that RA receptor isoforms were expressed in sheep amnion, and RA response elements (RAREs) were identified in ovine RARb and VEGF gene promoters. In ovine amnion cells, RA treatment upregulated RARb messenger RNA (mRNA) and increased VEGF transcript levels. In sheep fetuses, increases in IMA rate was associated with elevated VEGF mRNA levels in the amnion but not in the chorion. Further, RARb mRNA was positively correlated with VEGF mRNA levels in the amnion and not chorion. We conclude that an RA pathway is present in ovine fetal membranes and that RA is capable of inducing VEGF. The finding of a positive relationship between amnion VEGF and RARb during altered IMA rate suggests that the retinoid pathway may play a role through VEGF in regulating intramembranous transport across the amnion. Keywords RAR and RXR, sheep fetal membranes, intramembranous transport, amniotic fluid
Introduction During pregnancy, the amnion is a multifunctional tissue originating from the embryonic ectodermal layer. The amnion together with the underlying chorion encompasses the accumulated amniotic fluid serving as a protective enclosure to facilitate growth and maturation of the developing fetus. Early studies described the amniotic membrane as epithelial with transport characteristics.1-3 Subsequently, a role for the placental amnion in the regulation of amniotic fluid volume (AFV) has been proposed.4 In humans, the amnion is partitioned into 3 regions with distinct morphology and gene expression patterns5: placental amnion, reflected amnion juxtaposed to the membranous chorion, and amnion overlaying the umbilical cord.6 Recent studies have established the concept that AFV is regulated by vesicular transport pathways within the placental amnion7 to modulate uptake and transcytosis of amniotic fluid from the amniotic cavity into the fetoplacental circulation within the placental plate. This transport process is referred to as intramembranous absorpt
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