Abstract
Preeclampsia (PE) is a major cause of maternal mortality and morbidity, affecting 3–5% of all pregnancies. The Notch signaling pathway plays an important role during placental development, activating several target genes. Defects in the Notch pathway have adverse effect on placentation. The aim of this study was to investigate the expression of receptors NOTCH1,-2,-3,-4, ligands DLL1,-3,-4, JAG1,-2 and target genes HEY1,-2 in placental tissue samples from 20 late preterm or term pregnancies complicated by PE versus 20 normal pregnancies. mRNA levels of the studied molecules were measured by quantitative Real-Time PCR (qRT-PCR), while the protein expression of the intracellular domain of NOTCH2 (NICD2) and NOTCH3 (NICD3) was measured by Western Blot (WB). qRT-PCR analysis revealed that NOTCH1, NOTCH4 and DLL1 were not expressed in the placenta. On the contrary, NOTCH2, NOTCH3, DLL3, DLL4, JAG1, JAG2, HEY1 and HEY2 mRNA levels were downregulated in PE samples vs. controls (p<0.01). WB confirmed that NICD2 (p = 0.014) and NICD3 (p<0.001) protein levels were also lower in PE specimens. Statistical analysis revealed several significant associations: of NOTCH3 mRNA expression with smoking during pregnancy (p = 0.029), of NICD3 protein levels (p = 0.028) and DLL3 mRNA levels (p = 0.041) with birth weight centile, and of HEY2 transcript levels with parity (p = 0.034) and mode of delivery (p = 0.028). Our results suggest that Notch pathway downregulation is associated with PE. Further studies are required in order to determine the role of these molecules in PE pathogenesis and to evaluate their potential use for the early detection and treatment of PE.
Highlights
Preeclampsia (PE) affects 3–5% of all pregnancies worldwide and is a major cause of maternal mortality and morbidity [1]
Each of these proteins shows cell-typeand tissue-specific expression during development. This ligand-receptor interaction leads to the proteolytic cleavage and release of the NOTCH intracellular domain (NICD), which translocates to the nucleus, where it interacts with the DNA with the help of transcription factor RBPJK, inducing the expression of numerous target genes [5]
Our results revealed that NOTCH1, NOTCH4, and DLL1 were not expressed in the late preterm or term placentas of either women with normal pregnancies or women with pregnancies
Summary
Preeclampsia (PE) affects 3–5% of all pregnancies worldwide and is a major cause of maternal mortality and morbidity [1]. The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism, which is involved in cell fate decisions and pattern formation during development [3]. NOTCH1-4 receptors are single-pass transmembrane proteins that are activated by Delta (DLL1,-3,-4) and Jagged/Serrate (JAG1,-2) ligands [4]. Each of these proteins shows cell-typeand tissue-specific expression during development. This ligand-receptor interaction leads to the proteolytic cleavage and release of the NOTCH intracellular domain (NICD), which translocates to the nucleus, where it interacts with the DNA with the help of transcription factor RBPJK, inducing the expression of numerous target genes [5]
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