Circulating Cell-free Mitochondrial DNA In Normal Human Pregnancy and In Experimental Preeclampsia




Phillips, Nicole
Chaudhari, Sarika
Sprouse, Marc
Jarvis, Sara
Okada, Yoshiyuki
Morton, Jude
Davidge, Sandra
Fu, Qi
Goulopoulou, Styliani


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Background: Mitochondrial DNA (mtDNA) is a damage-associated molecular pattern (DAMP) with potent immunogenic and inflammatory properties. Circulating cell-free mtDNA is increased in various inflammatory conditions associated with intense cell apoptotic processes. Pregnancy is characterized by systemic inflammation and placental apoptosis, which increase with advancing gestational age. The temporal changes of cell-free mtDNA during healthy pregnancy and in pregnancies with preeclampsia are unknown. Hypothesis: Circulating cell free mtDNA increases with gestational age in pregnant women and these changes positively correlate with maternal cardiovascular responses and neonatal biometrics. In a rat model of preeclampsia, circulating mtDNA is increased compared to normotensive control rats. Methods: Normal Human Pregnancy: Maternal blood samples were collected at early pregnancy (≤ 8 weeks of gestation), late pregnancy (32-36 weeks), and postpartum (6-10 weeks after delivery) in healthy, normotensive, pregnant women (n=21). Experimental Model of Preeclampsia: Reduced uterine perfusion pressure (RUPP) was surgically induced in pregnant rats on gestational day (GD) 14. Maternal blood samples were collected from RUPP rats (n=11) and control rats (Sham, n=11) on GD20. Absolute real-time PCR quantification of mtDNA was performed on whole genomic extracts from maternal human and rat sera using TaqMan® probes and chemistry. Results: Normal Human Pregnancy: Circulating mtDNA in late pregnancy were greater compared to early pregnancy (0.02 ± 1.2 pg/μL vs. 0.04 ± 1.2 pg/μL, p=0.04) and remained elevated post-partum (0.03 ± 1.2 pg/μL). Both blood pressure and heart rate increased from early to late pregnancy and decreased postpartum (pExperimental Model of Preeclampsia: RUPP rats had increased circulating mtDNA as compared to the sham group (0.30 ± 0.04 copy number/µL vs. 0.18 ± 0.04 copy number/µL, p=0.03). Conclusions: In normal pregnant women, circulating mtDNA change with advancing gestational age and may reflect rates of placental cell apoptosis. In a rat model of preeclampsia associated with placental ischemia, circulating cell free mtDNA is elevated in late pregnancy. The temporal changes in mtDNA in preeclampsia and their functional role in normal and preeclamptic pregnancies need to be further evaluated.