There is consensus that
ischemia/reperfusion injury associated with
preeclampsia (PE) promotes both placental damage and the release of factors leading to maternal endothelium dysfunction, a hallmark of this potentially life-threatening syndrome. These factors include
plasminogen activator inhibitor-1 (PAI-1) and soluble fms-like
tyrosine kinase-1 (sFlt-1). The goal of this study was to further characterize placental factors involved in the pathophysiology of PE. Thus,
DNA microarray gene profiling was utilized to identify
mRNA differentially regulated in placentas from women with severe PE compared to both preterm (PC) and term control (TC) groups. Microarray studies detected an upregulation of
mRNA for
ceruloplasmin, a
copper-containing
iron transport protein with
antioxidant ferroxidase properties, in PE compared to PC and TC placentas, respectively. Quantitative real-time PCR confirmed these results by demonstrating significant increases in
ceruloplasmin mRNA in PE vs PC and TC placentas. Supporting previous reports, the expression of sFlt-1 and
PAI-1 were also upregulated in PE placentas. Immunohistochemistry localized
ceruloplasmin to the intervillous space in PE and PC placentas, whereas stronger syncytial staining was noted in PE. Western blotting confirmed a significant increase in
ceruloplasmin levels in placental tissue in PE compared to PC groups. PCR identified the presence of
mRNA for
ceruloplasmin in primary cultures of syncytiotrophoblasts, but not villous-derived fibroblasts, suggesting that syncytium is the site of
ceruloplasmin synthesis in placenta. Hypoxic treatment (1% O(2)) of syncytiotrophoblasts enhanced levels of
ceruloplasmin mRNA approximately 25-fold, a significantly greater upregulation than that noted for
PAI-1 and sFlt-1, suggesting that enhanced
ceruloplasmin expression is a sensitive marker of syncytial
hypoxia. We suggest that syncytial
ceruloplasmin and its associated
ferroxidase activity, induced by the
hypoxia accompanying severe PE, is important in an endogenous cellular program to mitigate the damaging effects of subsequent
reperfusion injury at this site.