Abstract
Fetal delivery of calcium, via the placenta, is crucial for appropriate skeletal mineralization. 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 vs. heaviest (LvH) placentas in a litter. In both models increased placental calcium transport was associated with normalization 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 hypothesized that PTHrP expression would be increased in LvH WT placentas, and in P0 vs. WTL. We used calcium pathway-focused PCR arrays to assess whether mechanisms underpinning these adaptations in LvH WT placentas, and in P0 vs. WTL, were similar. PTHrP protein expression was not different between LvH WT placentas at E18.5 but trended toward increased expression (139%; P = 0.06) in P0 vs. 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 vs. 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 vs. WTL (1.6- and 1.7-fold, respectively; P < 0.05). Signaling events underpinning adaptations in calcium transport are distinct between LvH placentas of WT mice and those in P0 vs. 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.
Highlights
Placental dysfunction, associated with reduced rates of nutrient uptake [1,2,3], is a major cause of fetal growth restriction (FGR), the failure of a fetus to reach its growth potential [4]
Expression of Parathyroid hormone-related protein (PTHrP) was not different between lightest compared with heaviest (LvH) WT placentas, but there was a trend toward increased expression in P0 vs. wild type littermates (WTL) placentas; PTHrP has been shown to influence placental calcium transport in most [32, 33, 36], but not all studies [47]
Any change in PTHrP expression in placentas near term may be important in the increased maternofetal calcium transfer observed in P0 vs. WTL
Summary
Placental dysfunction, associated with reduced rates of nutrient uptake [1,2,3], is a major cause of fetal growth restriction (FGR), the failure of a fetus to reach its growth potential [4]. Unlike the activity of other nutrient, and especially amino acid, transport systems that are reduced in placentas of growth restricted fetuses [1,2,3], the activity of PMCA is increased in human FGR [18] as is the maternofetal transfer of calcium in a rodent model of FGR, the placental-specific insulin-like growth factor 2 (P0) knockout mouse [19]. The gestational timing of this adaptation in WT mice was similar to that which we previously observed in the P0 knockout mouse [19], and points to a role for fetal nutrient demand in driving this adaptation via altered expression of placental calcium binding proteins These data showed that placental adaptations are an important feature of both normal and compromised fetal growth and help to ensure appropriate calcium acquisition relative to the size of the fetus. Using calcium pathway-focused PCR arrays we tested the hypothesis that placental mechanisms underpinning the adaptive increase in calcium transfer in WT mice and in P0 mice would be similar
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