Steroid sulfatase is increased in the placentas and whole blood of women with early-onset preeclampsia
Introduction
Preeclampsia is a serious hypertensive disorder complicating approximately 5% of pregnancies [1], [2], [3]. It is the single leading cause of maternal mortality [4], responsible for over 70,000 global maternal deaths every year [1]. The cost of this disease is compounded by limited effective preventative measures and a lack of adequate screening.
Preeclampsia has traditionally been considered a two-stage disease [5]. The first asymptomatic stage comprises abnormal placental implantation and failure of spiral artery remodeling. Resulting dysregulated placental perfusion and ischemia causes release of anti-angiogenic factors such as soluble fms-like Tyrosine Kinase 1 (sFlt1). sFlt1 disrupts the maternal endothelium by binding circulating angiogenic factors, resulting in the symptomatic second stage of the disease [6], [7], [8]. Clinically, preeclampsia manifests as a multi-system disorder affecting maternal vessels (causing hypertension and endothelial dysfunction), kidneys, liver, the haematological system, brain (causing seizures, or eclampsia) and the fetus (growth restriction).
The two-stage model underpins much of our understanding of the disease and it is clear that the placenta is central to the pathogenesis [9]. Using in silico analysis, we identified 137 genes that were highly expressed in the placenta relative to other non-malignant human tissues [10]. We reasoned that these Placental Specific Genes (PSGs) may be differentially altered in preeclamptic placenta and involved in the pathogenesis of the disease. Steroid Sulfatase (STS) is one of the 137 identified PSGs. In silico analysis suggests it is 34.4-fold more highly expressed in placenta compared to other human tissues [11].
STS is one of a larger family of 12 mammalian sulfatases that are encoded by the STS gene. STS has been shown to be responsible for the hydrolysis of abundant conjugated steroids converting them to active steroids with estrogenic properties [12]. While studies have identified a role for STS in breast cancer [13], [14], [15], its role in placentally-derived conditions such as preeclampsia has not been explored.
This study explores a role for STS in preeclampsia. We hypothesized that STS may be differentially expressed in preeclamptic placenta and play a functional role in the pathogenesis of the disease. We assessed this by characterising STS expression at the mRNA and protein level in preeclamptic placenta. We silenced STS in primary trophoblasts to examine the functional effect on sFlt1 secretion and syncytialisation. We also investigated whether STS mRNA is detectable in maternal whole blood.
Section snippets
Tissue collection
Women presenting to the Mercy Hospital for Women provided written and informed consent for placental tissue collection. Placentas were obtained from preterm pregnancies and those complicated by preterm preeclampsia. Preterm preeclampsia was diagnosed in accordance with American College of Obstetricians and Gynaecologists (ACOG) guidelines [16]. Samples were acquired from cases of preterm preeclampsia, defined as requiring delivery <34 weeks gestation. Control placentas were from women
Identification of genes significantly altered in preeclamptic placenta
We performed a PCR array (TLDA) of 45 PSGs, using placental RNA collected from preeclamptic (n = 12) and gestation-matched normotensive controls (n = 22). 10 genes were significantly altered in preeclamptic placentas relative to gestation matched normotensive controls including increased Vascular Endothelial Cadherin, EF-hand domain family member 1, syncytin, Pappalysin 2, High-temperature requirement serine protease A1, 17β Hydroxysteroid dehydrogenase type XI, Bone Morphogenic Protein 1,
Discussion
Preeclampsia is a serious disease associated with placental dysfunction. PSGs are differentially expressed in placentally-derived diseases such as FGR and preeclampsia [10]. Here we assessed the expression of 45 PSGs in preterm and preterm preeclamptic placentas and found significant increases in expression of 10 genes. STS was one of the 10 genes that was significantly altered in preeclamptic placenta in our preliminary studies and was chosen as a candidate for further investigation given no
Sources of funding
The National Health and Medical Research Council of Australia provided salary (#1062418 to T.K, #1050765 to S.T. and a Senior Principal Research Fellowship to PJF #1002559). N.H salary provided by CR Roper Fellowship. The Hudson Institute is supported by the Victorian Government's Operational Infrastructure Scheme.
Conflict of interest
The authors of this paper have no conflict of interest to declare.
Acknowledgements
The authors acknowledge Maria Alexiadis at the Hudson Institute of Medical Research for assistance with running the TLDA PCR Cards. The authors also acknowledge Clinical Research midwives Gabrielle Pell, Debra Jinks, Rachel Murdoch and Genevieve Christophers and the Obstetrics midwifery staff and patients at the Mercy Hospital for Women (Heidelberg) for their provision of placental tissue.
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