Ovine uterine space restriction alters placental transferrin receptor and fetal iron status during late pregnancy

Abstract

BackgroundFetal growth restriction is reported to be associated with impaired placental iron transport. Transferrin receptor (TfR) is a major placental iron transporter in humans, but is unstudied in sheep. TfR is regulated by both iron and nitric oxide (NO), the molecule produced by endothelial NOS (eNOS). We hypothesized that limited placental development downregulates both placental TfR and eNOS expression, thereby lowering fetal tissue iron.MethodsAn ovine surgical uterine space restriction (USR) model, combined with multifetal gestation, tested the extremes of uterine and placental adaptation. Blood, tissues, and placentomes from non-space restricted (NSR) singletons were compared to USR fetuses at 120 or 130 days of gestation (GD).ResultsWhen expressed proportionate to fetal weight, liver iron content did not differ while renal iron was higher in USR vs. NSR fetuses. Renal TfR protein expression did not differ, but placental TfR expression was lower in USR fetuses at GD130. Placental levels of TfR correlated to eNOS. TfR was localized throughout the placentome, including the hemophagous zone, implicating a role for TfR in ovine placental iron transport.ConclusionIn conclusion, fetal iron was regulated in an organ-specific fashion. In USR fetuses, NO-mediated placental adaptations may prevent the normal upregulation of placental TfR at GD130.

Local Effects of Pregnancy on Connexin Proteins That Mediate Ca 2+ -Associated Uterine Endothelial NO Synthesis

“…Restricting pregnancy to a single uterine horn 19, 20 only showed increased ipsilateral UBF possibly due to pregnancy specific uterine adaptations to local endogenous hormone secretion (e.g. estrogen, VEGF, etc).…”

“…Local ER and NO-mediated regulation of UBF was demonstrated by decreases in UBF in response to unilateral infusion of ER antagonist (ICI-182,780) or NOS inhibitor (L-NAME) 10, 16-18 . To better understand local UBF and eNOS regulation, we developed a unilateral model of pregnancy by isolating one uterine horn (nongravid) so that pregnancy is restricted only to the other horn (gravid) throughout gestation 19, 20 . UA endothelial cells from pregnant ewes (P-UAECs) 21 have sustained excitatory eNOS phosphorylation at serine 635 (P 635 ) with ATP treatment, suggesting this site is an important index of eNOS activity 22, 23 .…”

Dietary-induced gestational iron deficiency inhibits postnatal tissue iron delivery and postpones the cessation of active nephrogenesis in rats

“…After homogenisation in iron-free water (v/v) with an iron-free pestle homogenizer, non-heme iron concentration (μg g −1 wet weight) and tissue total non-heme iron allotment (μg) were quantified as described previously (Rebouche et al . 2004; Sun et al . 2013).…”

“…Glomerular surface area and glomerular density (mean number of glomeruli per mm 2 of cortex; Drake et al . 2009; Sun et al . 2013) measurements were determined in ×10 fields merged to reconstitute the whole cortex in Adobe Photoshop CS3 software (Adobe Systems, San Jose, CA, USA) and a 45° angle or ‘pie’ slice drawn from the geometric centre of the kidney.…”

Interactive effects of in vitro binge-like alcohol and ATP on umbilical endothelial nitric oxide synthase post-translational modifications and redox modulation

“…Many alcohol studies on eNOS have been performed in adult non-pregnant human or animal tissues; for instance, in vitro acute treatment of alcohol (0.1%, 3h) increased bovine aortic endothelial NO [7], whereas alcohol at 4 g/kg for 12 weeks decreased rat aortic eNOS expression, NO levels, and impaired vasorelaxation [8]. Intravenous infusion of alcohol in male and non-pregnant female rabbits [9] as well as in healthy human volunteers [10] dose-dependently decreased levels of exhaled NO. Among studies on fetoplacental cells, in vitro acute alcohol exposure (100 or 200 mM, 2h) decreased placental villi NO and cyclic GMP levels [11].…”