Severe Preeclampsia-Related Changes in Gene Expression at the Maternal-Fetal Interface Include Sialic Acid-Binding Immunoglobulin-Like Lectin-6 and Pappalysin-2

Abstract

Preeclampsia (PE), which affects 4-8% of human pregnancies, causes significant maternal and neonatal morbidity and mortality. Within the basal plate, placental cytotrophoblasts (CTBs) of fetal origin invade the uterus and extensively remodel the maternal vasculature. In PE, CTB invasion is often shallow, and vascular remodeling is rudimentary. To better understand possible causes, we conducted a global analysis of gene expression at the maternal-fetal interface in placental samples from women with PE (n = 12; 24-36 wk) vs. samples from women who delivered due to preterm labor with no evidence of infection (n = 11; 24-36 wk), a condition that our previous work showed is associated with normal CTB invasion. Using the HG-U133A&B Affymetrix GeneChip platform, and statistical significance set at log odds-ratio of B >0, 55 genes were differentially expressed in PE. They encoded proteins previously associated with PE [e.g. Flt-1 (vascular endothelial growth factor receptor-1), leptin, CRH, and inhibin] and novel molecules [e.g. sialic acid binding Ig-like lectin 6 (Siglec-6), a potential leptin receptor, and pappalysin-2 (PAPP-A2), a protease that cleaves IGF-binding proteins]. We used quantitative PCR to validate the expression patterns of a subset of the genes. At the protein level, we confirmed PE-related changes in the expression of Siglec-6 and PAPP-A2, which localized to invasive CTBs and syncytiotrophoblasts. Notably, Siglec-6 placental expression is uniquely human, as is spontaneous PE. The functional significance of these novel observations may provide new insights into the pathogenesis of PE, and assaying the circulating levels of these proteins could have clinical utility for predicting and/or diagnosing PE.

Plasma level of hydroxysteroid (17-β) dehydrogenase 1 in the second trimester is an independent risk factor for predicting preeclampsia after adjusting for the effects of mean blood pressure, bilateral notching and plasma level of soluble fms-like tyrosine kinase 1/placental growth factor ratio

“…26 In addition, in the current study, we revealed that the decrease of plasma levels of HSD17B1 may precede the clinical onset of PE in the second trimester, without relating to the abnormalities of angiogenesis-related factors. As HSD17B1 is a steroidogenetic enzyme HSD17B1 as an independent risk factor for preeclampsia A Ohkuchi et al catalyzing the conversion of estrone to 17b-estradiol, 27,28 the decrease of 17b-estradiol might be involved in the genesis of PE.…”

PAPPA2 is increased in severe early onset pre-eclampsia and upregulated with hypoxia

“…The collective cohort size in all reports demonstrating PAPPA2 protein is increased in severe preterm PE has thus far been limited to only 30 (Nishizawa et al 2008;Winn et al 2009). Therefore, we thought it was important to provide independent confirmation of this finding.…”

“…However, the present study appears to be the first to comprehensively compare PAPPA2 immunohistochemistry between PT, PE and term samples and to observe a lack of staining in term samples. Although variable, placental PAPPA2 mRNA levels have also been reported to decline with gestation (Winn et al 2009) and PAPPA2 has been shown to be a cleavage protease for insulin-like growth factor (IGF) binding protein 5 (Wang et al 2009) bioavailability. Thus, the decline in placental PAPPA2 protein observed at term in our immunohistochemical samples is possibly a result of the decreased placental growth occurring during this phase of pregnancy.…”

“…Importantly, recent reports demonstrate a link between PAPPA2 and PE (Nishizawa et al 2008;Winn et al 2009;Paiva et al 2011). However, the evidence showing raised PAPPA2 protein in severe preterm PE (responsible for most of the morbidity caused by this disease) is limited to 30 cases described to date (Nishizawa et al 2008;Winn et al 2009). Thus, this association merits further independent validation.…”

Identification of ACOX2 as a shared genetic risk factor for preeclampsia and cardiovascular disease

“…9 Many genes have also been identified to be differentially expressed in the placenta or in decidual tissues between women with PE and women with normal pregnancies. [10][11][12] However, it is still unknown whether such differential gene expression is causal or is secondary to the disorder.…”