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Front. Endocrinol. | doi: 10.3389/fendo.2018.00671

Mechanisms Underpinning Adaptations In Placental Calcium Transport In Normal Mice And Those With Fetal Growth Restriction

 Christina E. Hayward1, 2,  Kirsty R. McIntyre1, 2, Susan L. Greenwood1, 2, Colin P. Sibley1, 2 and  Mark R. Dilworth1, 2*
  • 1Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
  • 2Manchester University NHS Foundation Trust, St Mary's Hospital, Manchester Academic Health Science Centre, United Kingdom

Fetal delivery of calcium, via the placenta, is crucial for appropriate skeletal mineralisation. We have previously demonstrated that maternofetal calcium transport, per gram placenta, is increased in the placental specific insulin-like growth factor 2 knockout mouse (P0) model of fetal growth restriction (FGR) compared to wild type littermates (WTL). This effect was mirrored in wild-type (WT) mice comparing lightest versus heaviest (LvH) placentas in a litter. In both models increased placental calcium transport was associated with normalisation of fetal calcium content. Despite this adaptation being observed in small normal (WT), and small dysfunctional (P0) placentas, mechanisms underpinning these changes remain unknown. Parathyroid hormone-related protein (PTHrP), elevated in cord blood in FGR and known to stimulate plasma membrane calcium ATPase, might be important. We hypothesised that PTHrP expression would be increased in LvH WT placentas, and in P0 versus WTL. We used calcium pathway-focused PCR arrays to assess whether mechanisms underpinning these adaptations in LvH WT placentas, and in P0 versus WTL, were similar.
PTHrP protein expression was not different between LvH WT placentas at E18.5 but trended towards increased expression (139%; P=0.06) in P0 versus WTL. PCR arrays demonstrated that four genes were differentially expressed in LvH WT placentas including increased expression of the calcium-binding protein calmodulin 1 (1.6 fold; P<0.05). Twenty-four genes were differentially expressed in placentas of P0 versus WTL; significant reductions were observed in expression of S100 calcium binding protein G (2 fold; P<0.01), parathyroid hormone 1 receptor (1.7 fold; P<0.01) and PTHrP (2 fold; P<0.05), whilst serum/glucocorticoid-regulated kinase 1 (SGK1), a regulator of nutrient transporters, was increased (1.4 fold; P<0.05). Tartrate resistant acid phosphatase 5 (TRAP5 encoded by Acp5) was reduced in placentas of both LvH WT and P0 versus WTL (1.6 and 1.7 fold respectively; P<0.05).
Signalling events underpinning adaptations in calcium transport are distinct between LvH placentas of WT mice and those in P0 v WTL. Calcium binding proteins appear important in functional adaptations in the former whilst PTHrP and SGK1 are also implicated in the latter. These data facilitate understanding of mechanisms underpinning placental calcium transport adaptation in normal and growth restricted fetuses.

Keywords: Placenta, Calcium, adaptation, IUGR Intrauterine growth restriction, Fetal growth restriction (FGR), Mouse

Received: 16 Sep 2018; Accepted: 29 Oct 2018.

Edited by:

Elke Winterhager, Universität Duisburg-Essen, Germany

Reviewed by:

Dana M. Savulescu, Wits Health Consortium (WHC), South Africa
Amanda Sferruzzi-perri, University of Cambridge, United Kingdom  

Copyright: © 2018 Hayward, McIntyre, Greenwood, Sibley and Dilworth. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Mark R. Dilworth, University of Manchester, Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester, M13 9PL, North East England, United Kingdom,