Spontaneous superimposed preeclampsia: chronology and expression unveiled by temporal transcriptomic analysis

Abstract

Preeclampsia (PE), a multifactorial pregnancy-specific syndrome accounting for up to 8% of pregnancy complications, is a leading cause of maternal and fetal morbidity and mortality. PE is also associated with long-term risk of hypertension and stroke for both mother and fetus. Currently, the only “cure” is delivery of the baby and placenta, largely because the pathogenesis of PE is not yet fully understood. PE is associated with impaired vascular remodeling at the maternal-fetal interface and placental insufficiency; however, specific factors contributing to this impairment have not been identified. To identify molecular pathways involved in PE, we examined temporal transcriptomic changes occurring within the uterus, uterine implantation sites, and placentae from the Dahl salt-sensitive (Dahl S) rat model of superimposed PE compared with Sprague Dawley (SD) rats. We hypothesized that targeted gene analysis and whole transcriptome analysis would identify genetic factors that contribute to development of the preeclamptic phenotype in the Dahl S rat and unveil novel biomarkers, therapeutic targets, and mechanistic pathways in PE. Quantitative real-time PCR (qRT-PCR) and whole genome microarray analysis were performed on isolated total RNA from uterus ( day 0), uterine implantation sites ( days 7 and 10), and placenta ( days 14 and 20). We found 624, 332, 185, and 366 genes to be differentially expressed between Dahl S (PE) and SD (normal pregnancy) on days 0, 7, 10, and 14, respectively. Our data revealed numerous pathways that may play a role in the pathophysiology of spontaneous superimposed PE and allow for further investigation of novel therapeutic targets and biomarker development.

l‐Citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

“…Citrulline up‐regulated the gene expression of SIRT1, which is an important stress‐response protein that modulates feto‐placental vascular development (Pham et al, 2018) (Figure 6c). The gene expression of enzymes related to lipid metabolism, including paraoxonase 2 ( Pon2 ), protein kinase AMP‐activated non‐catalytic subunit γ2 ( Prkag2 ), and phospholipase A ( Pla2 ), was recently reported to be differentially expressed in the placentas of Sprague–Dawley (SD) rats and DSSR (Maeda et al, 2019). Interestingly, the expression of Pon2 and Pla2 was significantly up‐regulated in citrulline‐treated DSSR (Figure 6d).…”

“…However, excessive flux of lipids could promote oxidative stress and inflammatory cascades, contributing to preeclampsia (Tenorio et al, 2019). A recent temporal transcriptomic analysis study in DSSR has identified a cluster of aberrantly regulated genes involved in lipid and fatty acid metabolism, including the apolipoprotein family, Pon2 , Prkag2 and Pla2 (Maeda et al, 2019). PON2 is an important antioxidant enzyme that is associated with lipid metabolism and insulin sensitivity (Manco et al, 2021).…”

L-citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

“…Citrulline upregulated the gene expression of SIRT1, which is an important stress-response protein that modulates feto-placental vascular development 44 (Figure 6C) . The gene expression of enzymes related to lipid metabolism, including the paraoxonase 2 (PON2), protein kinase AMP-Activated non-catalytic subunit gamma 2 (Prkag2), phospholipase A2 (Pla2) was recently reported differentially expressed in placentas between Sprague Dawley (SD) rats and DSSR 45 . Interestingly, the gene expression of PON2 and PLA2 was significantly upregulated in citrulline-treated DSSR (Figure 6D) .…”

“…In a recent temporal transcriptomic analysis study, many differentially expressed genes between SD rats and DSSR are reported 45 . Among these genes, we have noticed a cluster of genes which are genes involved in lipid and fatty acid metabolism, including the apolipoprotein family, Pon2, Prkag2 and Pla2.…”

Placental Glycoredox Dysregulation Associated with Disease Progression in an Animal Model of Superimposed Preeclampsia

“…At the second stage, ischemia–reperfusion damage of the placenta with oxidative/endoplasmic reticulum stress enhances the release of soluble mediators that trigger the systemic inflammatory cascade and endothelial dysfunction ultimately responsible for the maternal syndrome [ 6 , 7 ]. While the specific mechanisms promoting SPE are still largely unknown, evidence from clinical studies [ 8 , 9 , 10 ] and, more recently, animal models of chronic hypertension [ 11 , 12 , 13 ] point out to the involvement of placental cellular and molecular pathways largely overlapping those described for the de novo syndrome.…”