The Impact of Maternal-Fetal Genetic Conflict Situations on the Pathogenesis of Preeclampsia

Abstract

Preeclampsia leads to maternal and perinatal morbidity and mortality. The literature in English was reviewed to summarize recent advances in understanding the global gene expression changes in the pathogenesis of preeclampsia. We identified at least eight consistently enriched categories, relating to pregnancy maintenance, metabolism, oxidative stress, cell cycle regulation, implantation, decidualization, immune modulation, and vascular function. Expression profiling in preeclampsia placenta and normal placenta revealed 140 transcripts that were significantly differentially expressed, 30 (21.4%) of which were evolved for the protection of the mother, approximately three times less than the number of genes evolved for the benefit of the fetus [110 genes (78.6%)] in preeclampsia placenta versus normal placenta. The genome-wide analysis emphasizes the dysfunctional decidualization as the main mechanism involved in the development of preeclampsia. These genetic signaling events may occur from an imbalance in the maternal-fetal genetic response in the affected placenta. This is to our knowledge the first report on the pathogenesis of preeclampsia, in which preeclampsia may occur as a genetic consequence of maternal-fetal conflict situations during the early decidualization process.

Immune‑related pathophysiological causes relevant to a subset of patients with preeclampsia (Review)

“…Although the placenta is the central organ for pathogenesis, epigenetic mechanisms in the placenta highlight the importance of a fine-tune orchestration of DNA methylation, miRNAs, histone modifications and chromatin structure (83). Recent epigenetic mechanisms associated with the dysfunction and dysregulation of decidualization-related genes have a critical impact on the susceptibility, development and progression of complex diseases, such as miscarriage, preterm birth, or preeclampsia (35,36,40). Furthermore, a previous study demonstrated that half of the decidualization-related genes in preeclampsia-affected placentas are downregulated and are also located within and in close proximity to known imprinted genes, suggesting an association between an epigenetic process and genomic imprinting in preeclampsia (36).…”

“…Compared to microarray-based analysis, RNA-seq can detect splicing isoforms and somatic mutations by taking advantage of a higher coverage and greater resolution (34). These approaches have identified the gene expression signatures and have predicted key pathways involved in preeclampsia-affected placentas (31,32,(35)(36)(37)(38). Although to date, at least to the best of our knowledge, there are relatively few available studies which have conducted gene expression analysis in preeclampsia-affected placentas using the RNA-seq method (32,33), a number of differentially expressed genes and their pathways have been shown to have the same direction of change.…”

“…Low maternal serum levels of pappalysin 1 (PAPP-A), galectin 13 (placental protein 13; PP13) and insulin like growth factor 1 (IGF-I), and high levels of homocysteine, adrenomedullin A (ADMA), soluble endoglin (sEng), LEP, sFlt-1, inhibin A and activin A are predictive of emerging preeclampsia (39). A majority of studies focusing on preeclampsia have shared several overlapping genetic findings on defective decidualization (35,36,40). Abnormal decidualization leads to a decreased EVT invasion and to the development of preeclampsia, which corroborates the concept of the endometrial antecedents of preeclampsia (40,41).…”

“…Second, Gene Ontology enrichment analysis and functional ingenuity pathway analysis have been used to identify potential signaling pathways, suggesting that various physiological processes, such as chronic inflammation characterized by local or systemic oxidative stress (12,16) and innate and adaptive immune system (13,14), angiogenesis, hypoxia, apoptosis and placental development are implicated in the pathophysiology of preeclampsia (15). The following biological processes are also enriched in preeclampsia: Metabolism, cell cycle regulation, implantation, decidualization, cell-cell adhesion, the response to cAMP, the transforming growth factor (TGF)-β signaling pathway, Wnt signaling pathway and the Hippo signaling pathway (35,(42)(43)(44)(45). The abnormal spiral artery remodeling leads to a state of relative ischemia and to an increase in oxidative stress.…”

HRG C633T polymorphism and risk of gestational hypertensive disorders: a pilot study

“…The latter results in maternal systemic disease through primary mediators, including oxidative stress and inflammation, and also secondary mediators, including modifiers of endothelial function and angiogenesis [ 5 ], leading to the clinical manifestation of preeclampsia. Genetic studies, such as microarray-based gene expression profiling studies, have been employed in the investigation of the pathogenesis of preeclampsia and differentially expressed genes have been identified [ 6 , 7 ].…”