Molecular Mechanisms of Preeclampsia

T, Hod; Cerdeira, Ana Sofia; Sa, Karumanchi

doi:10.1101/cshperspect.a023473

Cited by 147 publications

(113 citation statements)

References 180 publications

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“…This devastating pregnancy complication affects 5-8 % of all pregnancies worldwide and is characterized by de novo onset of hypertension and proteinuria in pregnant women [1][2][3][4][5][6][7][8][9][10]. The new clinical definition also includes severe hypertension and end-organ dysfunction which may or may not occur in conjunction with proteinuria after 20 weeks of gestation [2].…”

Section: Introductionmentioning

confidence: 97%

Preeclampsia and health risks later in life: an immunological link

Cheng

Sharma

2016

Semin Immunopathol

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Pregnancy represents a period of physiological stress, and although this stress is experienced for a very modest portion of life, it is now recognized as a window to women's future health, often by unmasking predispositions to conditions that only become symptomatic later in life. In normal pregnancy, the mother experiences mild metabolic syndrome-like condition through week 20 of gestation. A pronounced phenotype of metabolic syndrome may program pregnancy complications such as preeclampsia. Preeclampsia is a serious complication with a myriad of manifestations for mother and offspring. This pregnancy syndrome is a polygenic disease and has been now linked to higher incidence of cardiovascular disease, diabetes, and several other disorders associated with vulnerable organs. Furthermore, the offspring born to preeclamptic mothers also exhibit an elevated risk of cardiovascular disease, stroke, and mental disorders during adulthood. This suggests that preeclampsia not only exposes the mother and the fetus to complications during pregnancy but also programs chronic diseases in later life. The etiology of preeclampsia is thought to be primarily associated with poor placentation and entails excessive maternal inflammation and endothelial dysfunction. It is well established now that the maternal immune system and the placenta are involved in a highly choreographed cross-talk that underlies adequate spiral artery remodeling required for uteroplacental perfusion and free flow of nutrients to the fetus. Since normal pregnancy is associated with a sequence of events represented by temporal events of inflammation (implantation), anti-inflammation (gestation), and inflammation (parturition), it is quite possible that unscheduled alterations in these regulatory responses may lead to pathologic consequences. Although it is not clear whether immunological alterations occur early in pregnancy, it is proposed that dysregulated systemic and placental immunity contribute to impaired angiogenesis and the onset of preeclampsia. This review will focus on important aspects of the immune system that coordinate with placental dysfunction to program preeclampsia and influence health in later life.

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Section: Introductionmentioning

confidence: 97%

Preeclampsia and health risks later in life: an immunological link

Cheng

Sharma

2016

Semin Immunopathol

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“…18 Adenosine is a key signaling molecule that orchestrates the cellular response to hypoxia, energy depletion, and tissue damage by the activation of G-protein-coupled cell surface receptors. Recently, we demonstrated that placental adenosine is elevated in patients with preeclampsia.…”

Section: Hypertensionmentioning

confidence: 99%

Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia

Huang

Iriyama

et al. 2017

Hypertension

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Consistent with this, detailed analysis of DNA from preeclampsia placentas showed that hypomethylation at specific promoter regions was associated with increased expression of specific genes that may contribute to the pathophysiology of Abstract-Preeclampsia is a prevalent pregnancy hypertensive disease with both maternal and fetal morbidity and mortality.Emerging evidence indicates that global placental DNA hypomethylation is observed in patients with preeclampsia and is linked to altered gene expression and disease development. However, the molecular basis underlying placental epigenetic changes in preeclampsia remains unclear. Using 2 independent experimental models of preeclampsia, adenosine deaminase-deficient mice and a pathogenic autoantibody-induced mouse model of preeclampsia, we demonstrate that elevated placental adenosine not only induces hallmark features of preeclampsia but also causes placental DNA hypomethylation. The use of genetic approaches to express an adenosine deaminase minigene specifically in placentas, or adenosine deaminase enzyme replacement therapy, restored placental adenosine to normal levels, attenuated preeclampsia features, and abolished placental DNA hypomethylation in adenosine deaminase-deficient mice. Genetic deletion of CD73 (an ectonucleotidase that converts AMP to adenosine) prevented the elevation of placental adenosine in the autoantibodyinduced preeclampsia mouse model and ameliorated preeclampsia features and placental DNA hypomethylation.Immunohistochemical studies revealed that elevated placental adenosine-mediated DNA hypomethylation predominantly occurs in spongiotrophoblasts and labyrinthine trophoblasts and that this effect is independent of A2B adenosine receptor activation in both preeclampsia models. Extending our mouse findings to humans, we used cultured human trophoblasts to demonstrate that adenosine functions intracellularly and induces DNA hypomethylation without A2B adenosine receptor activation. Altogether, both mouse and human studies reveal novel mechanisms underlying placental DNA hypomethylation and potential therapeutic approaches for preeclampsia. (Hypertension. 2017;70:209-218.

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“…There have been many studies on the etiology of preeclampsia (Lwaleed et al, 2011); however, the pathogenesis of pre-eclampsia remains unclear. Many factors play important roles in the development of pre-eclampsia, such as preexisting hypertension, diabetes, high body mass index and obesity (Das, 2015;Hod et al, 2015;Mol et al, 2016). Pre-eclampsia in 35% of pregnant women is reportedly resulted from genetic factors (Hod et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Many factors play important roles in the development of pre-eclampsia, such as preexisting hypertension, diabetes, high body mass index and obesity (Das, 2015;Hod et al, 2015;Mol et al, 2016). Pre-eclampsia in 35% of pregnant women is reportedly resulted from genetic factors (Hod et al, 2015). Many genetic factors influence the pathogenesis of pre-eclampsia, such as glutathione S-transferase pi 1, glutathione peroxidase 1, matrix metalloproteinase-9, interleukin-8, tumor necrosis factor-a, interleukin-1-b, insulin receptor genes (Gao et al, 2016;Sun et al, 2016a,b;Tavakkol Afshari et al, 2016;Andraweera et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Association between interleukin-4 polymorphisms and risk of pre-eclampsia in a population of Chinese pregnant women

Chen¹,

Zhong²,

Yu³

2017

Genet. Mol. Res.

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ABSTRACT. Preeclampsia is a common disease unique to pregnant women, and its development involves many genetics l factors. IL-4 is an important regulatory factor of the Th2 cellular immune response, and plays an important role in the induction of placental growth. In this study, we investigated the relationship between IL-4 C-590T, C+33T and G-1098T polymorphisms and risk of pre-eclampsia in a population of pregnant women. A case-control study of 196 pregnant women with pre-eclampsia and 257 healthy controls was conducted. Genotyping of IL-4 C-590T, C+33T and G-1098T was performed by polymerase chain reaction-restriction fragment length polymorphism. We observed that the TT genotype, compared to the CC genotype, of IL-4 C-590T harbored a lower risk of pre-eclampsia; adjusted OR (95%CI) was 0.29 (0.11-0.81). The CT+TT genotype, compared to the CC genotype, harbored a lower risk of pre-eclampsia (adjusted OR = 0.50, 95%CI = 0.30-0.84) in the dominant model. In the recessive model, the TT genotype, compared to the CC+CT genotype, harbored a lower risk of pre-eclampsia (adjusted OR = 0.31, 95%CI = 0.11-0.86). However, 2 J. Chen et al. Genetics and Molecular Research 16 (2): gmr16029218 no significant correlation was observed between the IL-4 C+33T and G-1098T polymorphisms and risk of pre-eclampsia in three genetic models. In conclusion, IL-4 C-590T polymorphism could be used as a predictive risk factor for pre-eclampsia.

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Molecular Mechanisms of Preeclampsia

Cited by 147 publications

References 180 publications

Preeclampsia and health risks later in life: an immunological link

Preeclampsia and health risks later in life: an immunological link

Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia

Association between interleukin-4 polymorphisms and risk of pre-eclampsia in a population of Chinese pregnant women

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