Abstract 18695: Elevated Intracellular Adenosine Induces Placental DNA Hypomethylation and Contributes to Pathophysiology of Preeclampsia

    loading  Checking for direct PDF access through Ovid


Preeclampsia (PE) is a prevalent pregnancy hypertensive disease with both maternal and fetal morbidity and mortality. Previous studies indicate that elevated extracellular placental adenosine (Ado) contributes to the PE features by A2B receptor (ADORA2B) signaling; Accumulated intracellular Ado reverses DNA hypermethylation in epileptic rat model; Global placental DNA hypomethylation is observed in PE patients and linked to disease development. We hypothesize that increased intracellular Ado leads to the pathogenic DNA hypomethylation in PE placentas. Using two independent experimental models, adenosine deaminase (ADA) deficiency and the pathogenic autoantibody induced PE mice, we demonstrate that elevated placental Ado (ADA: 40±5 vs WT: 9±1; PE-IgG: 16±4 vs NT-IgG: 4±3nmole/mg protein; p<0.05, n=5) induces the key PE feature hypertension (ΔSBP: ADA: 25±3 vs WT: 2±1; PE-IgG: 21±3 vs NT-IgG: 3±1 mmHg; p<0.05, n=5) and placental DNA hypomethylation (ADA: 0.3±0.2% vs WT: 0.9±0.1%; PE-IgG: 0.5±0.2% vs NT-IgG: 1±0.2% 5mC DNA; p<0.05, n=5). Placental expression of an ADA minigene, CD73 deletion, or PEG-ADA therapy respectively repressed the increase in placental adenosine (11±2/1±1/7±2nmole/mg protein), ΔSBP (5±2/1±0/4±1mmHg) and placental DNA hypomethylation (0.7±0.2%/1.1±0.1%/0.9±0.2% 5mC DNA) in ADA deficient or PE-IgG treated mice (n=5, p<0.05 vs ADA-/-/PE-IgG). Immunohistochemical studies reveal that elevated placental adenosine-mediated DNA hypomethylation predominantly occurs in spongiotrophoblasts and labyrinthine trophoblasts in both PE models. We used cultured human trophoblasts to demonstrate that adenosine functions intracellularly and induces DNA hypomethylation without ADORA2B activation. Altogether, our in vivo and in vitro studies reveal novel DNA hypomethylation mechanisms underlying PE pathogenesis and suggest potential therapeutic approaches for the disease.

Related Topics

    loading  Loading Related Articles