Placental expression of ceruloplasmin in pregnancies complicated by severe preeclampsia.

The precise etiology of the maternal syndrome of pre-eclampsia (PE) remains unknown. There is consensus that PE as well as many cases of idiopathic intrauterine growth restriction (IUGR), are strongly associated with failed conversion of maternal endometrial spiral arteries in the placental bed.1 This failure precludes physiological development of the low-resistance/high-capacitance uteroplacental circulation observed in uncomplicated pregnancies.2,3 Whether this is due to shallow trophoblast invasion and/or to decidual factors remains the subject of debate.1 It is suggested that hypoxia and/or reperfusion injury at the maternal—placental interface in PE leads to the release of soluble syncytiotrophoblast (SCT; ie the outer layer of the trophoblast in direct contact with maternal blood) factors including eicosanoids,4 peroxides,5,6 cytokines,7,8 SCT microparticles,9,10 soluble fms-like tyrosine kinase-1 (sFlt-1),11 endoglin,12 and plasminogen activator inhibitor-1 (PAI-1).13 These factors are postulated to contribute to placental damage and maternal endothelial dysfunction, hallmarks of PE, although their relative contributions in promoting clinical features of PE (ie maternal proteinuria and hypertension) remain to be determined. The mechanism promoting the increased release of the abovementioned products by SCT in PE is largely unknown, although there is clear evidence of hypoxia-driven gene expression as well as oxidative damage in placentas from women with PE and idiopathic IUGR.14–16 Placental levels of the antiangiogenic factors, sFlt-1 and soluble endoglin, as well as the antifibrinolytic factor PAI-1, are all increased in pregnancies with PE.11–13 Conversely, levels of PAI-2, a major SCT protein, were lower in placentas from women with PE.13 Elevated expression of PAI-1 in SCT was specifically correlated with aberrantly high levels of intervillous fibrin and placental infarcts in patients with PE.13 The PAI-1, sFlt-1, and endoglin genes contain hypoxia response elements in their promoters and their expression in placental cultures is increased by hypoxia.17–19 It is known that the superoxide anion, the most common reactive oxygen species (ROS) can combine with nitric oxide to produce peroxynitrite anions which damage proteins.5 Increased placental nitrosylation of proteins and oxidative stress is a biochemical marker of PE.14,15 In addition, ROS-associated lipid peroxidation is enhanced in placental villi from pregnancies complicated by PE.4,20 Placental adaptations to the presence of damaging oxygen radicals generated during hypoxia/reperfusion injury associated with PE may include activation of endogenous antioxidant enzymes including catalase21 and glutathione peroxidase.22 The goal of the current study was to further characterize PE-associated placental pathophysiology. Gene profiling analysis of placental tissues was used to compare patterns of gene expression in placentas derived from women with PE compared to both preterm and term controls (PC and TC, respectively). This strategy revealed increased expression of ceruloplasmin, a copper-containing iron transport protein with ferroxidase activity,23,24 in PE compared to both PC and TC placentas. Validation of gene profiling results was accomplished by comparing placental expression of ceruloplasmin to that of sFlt-1 and PAI-1, which have been previously documented to be induced in PE. The likely cellular source of placental ceruloplasmin was then elucidated using placental tissue and primary cell cultures. Finally, modulation of ceruloplasmin expression by hypoxia was investigated, revealing a potential mechanism through which placental ceruloplasmin expression may be upregulated in pregnancies complicated by PE.