Serum From Preeclamptic Women Triggers Endoplasmic Reticulum Stress Pathway and Expression of Angiogenic Factors in Trophoblast Cells

Abstract

Preeclampsia (PE) is a hypertensive disease of pregnancy-associated with placental cell death and endoplasmic reticulum (ER) stress. It is unknown whether systemic factors aggravate placental dysfunction. We investigated whether serum factors in pregnant women with PE activate ER stress and unfolded protein responses (UPRs) in placental explants and trophoblast cells lineage. We cultured placental explants from third-trimester term placentas from control non-preeclamptic (NPE) pregnant women with serum from women with PE or controls (NPE). In PE-treated explants, there was a significant increase in gene expression of GADD34, CHOP, and SDF2. At the protein level, GRP78, SDF2, p-eIF2α, and p-eIF2α/eIF2α ratio were also augmented in treated explants. Assays were also performed in HTR8/SV-neo trophoblast cell line to characterize the putative participation of trophoblast cells. In PE serum-treated protein levels of p-eIF2a and the ratio p-elF2 α/elF2α increased after 12 h of treatment, while the gene expression of GADD34, ATF4, and CHOP was greater than control. Increased expression of SDF2 was also detected after 24 h-cultured HTR8/SV-neo cells. PE serum increased sFLT1 gene expression and decreased PlGF gene expression in placental explants. Morphologically, PE serum increased the number of syncytial knots and reduced placental cell metabolism and viability. Analysis of the serum of pregnant women with PE through Raman spectroscopy showed changes in amino acids, carotenoids, lipids, and DNA/RNA, which may be associated with the induction of ER stress found in chorionic villi treated with this serum. In conclusion, this study provides evidence that the serum of pregnant women with PE may impact placental villi changing its morphology, viability, and secreted functional factors while triggers ER stress and an UPR. The differences between PE and control sera include molecules acting as inducing factors in these processes. In summary, the results obtained in our assays suggest that after the development of PE, the serum profile of pregnant women may be an additional factor that feeds a continuous imbalance of placental homeostasis. In addition, this study may expand the possibilities for understanding the pathogenesis of this disorder.

Aβ1-42 stimulates an increase in autophagic activity through tunicamycin-induced endoplasmic reticulum stress in HTR-8/SVneo cells and pre-eclampsia

“…ER stress rises upon pathological stimuli that disrupt protein folding processes, accumulating misfolded proteins in the ER. Accumulating evidence has proven the close association between ER stress and PE [31][32]. To clear misfolded and aggregated proteins, a panel of signaling pathways is activated to maintain the balance of the ER stress, a phenomenon known as UPR.…”

Dynamic risk prediction models for different subtypes of hypertensive disorders in pregnancy

“…PlGF is a member of the vascular endothelial growth factor family and has important functions in regulating placental trophoblast and endothelial cell function ( 35 ). Numerous studies have shown that PlGF is a risk factor for HDP and has a predictive value for preeclampsia in particular ( 36 , 37 ). PlGF was tested significant only in the stepwise regression model for the early-onset preeclampsia, which indicated a significant predictive effect of PlGF on the early-onset preeclampsia ( Table 13 ).…”

Literature Review: The sFlt1/PlGF Ratio and Pregestational Maternal Comorbidities: New Risk Factors to Predict Pre-Eclampsia

“…Dramatically increasing the sFlt1/PlGF ratio can lead to pathological changes that are typical to pre-eclampsia: placental abruption [ 22 ], placental hypoxia [ 23 ], ischemic placental disease [ 24 ], placental vascular lesions [ 25 ], oxidative stress [ 26 , 27 ], endoplasmic reticulum stress [ 23 , 28 ], and maternal endothelial sensitization [ 23 ] ( Figure 1 ). These changes can lead to ectopic pregnancy and a missed abortion [ 29 ] but do not necessarily lead to them.…”