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

Abstract

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.

Reciprocal upregulation of hypoxia‐inducible factor‐1α and persistently enhanced placental adenosine signaling contribute to the pathogenesis of preeclampsia

“…Roles of intracellular adenosine under the physiologic and pathologic conditions remain largely unknown. Recently, Huang et al reported that accumulated intracellular adenosine causes global placental DNA hypomethylation that is associated with PE . Aberrant gene expression in the placenta, due to the epigenetic modulation caused by the changes in DNA methylation status, is widely considered to be involved in the PE pathophysiology .…”

“…Recently, Huang et al reported that accumulated intracellular adenosine causes global placental DNA hypomethylation that is associated with PE. 32 Aberrant gene expression in the placenta, due to the epigenetic modulation caused by the changes in DNA methylation status, is widely considered to be involved in the PE pathophysiology. 33,34 Huang et al showed that placental DNA hypomethylation status related to PE can be induced independent of ADORA2B activation, through the uptake of adenosine into the cytoplasm by equilibrative nucleoside transporters (ENTs).…”

Pregnancy exposure to atmospheric pollution and meteorological conditions and placental DNA methylation

“…ADORA2B, encoding the Adenosine A2B receptor, was shown to play a role in placental development and possibly in the pathophysiology of hypoxia and preeclampsia (PE) in pregnant women (Acurio et al, 2014;Darashchonak et al, 2014;Jia et al, 2012), a pathology which has also been associated with air pollution exposure during pregnancy (M. Pedersen et al, 2014). In both mice and humans, it has been demonstrated that activation of ADORA2B signalling contributes to the pathogenesis of PE (Huang et al, 2017), to small foetuses, small placentas and foetal growth restriction (Iriyama et al, 2015). The molecular basis of the functional link and relationship between ADORA2B gene and placenta DNA methylation, and the involvement of the ADORA2B protein in PE and birth outcomes are questions to be addressed in future investigations.…”

Metabolomic and molecular insights into sickle cell disease and innovative therapies

“…[28][29][30] However, persistently elevated adenosine can be detrimental and contribute to multiple disease conditions, such pulmonary fibrosis, chronic kidney disease, and preeclampsia. [31][32][33][34][35] Adenosine signals via 4 G protein-coupled receptors, ADORA1, ADORA2A, ADORA2B, and ADORA3, which are expressed in a variety of cell types. 36 Among the 4 adenosine receptors, ADORA2B has the lowest affinity for adenosine and is activated by substantial accumulation of extracellular adenosine.…”