OS 05-05 Nrf2 DEFICIENCY ALLEVIATES PERINATAL COMPLICATIONS IN PREGNANCY-ASSOCIATED HYPERTENSION MICE VIA ENHANCING PLACENTAL ANGIOGENESIS

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Abstract

Objective:

Placental activation of the renin-angiotensin system (RAS) plays an important role in pathogenesis of preeclampsia. RAS induces reactive oxygen species (ROS) production by activating NADPH oxidases. Keap1-Nrf2 system is a critical regulator for cellular anti-oxidative stress response through controlling transcription of antioxidant genes. This study has explored the relationship between RAS-induced ROS signaling and Keap1-Nrf2 system in preeclampsia.

Design and Method:

To examine the contribution of Keap1-Nrf2 system to preeclampsia pathology, we generated transgenic mouse models of preeclampsia/pregnancy-associated hypertension (PAH mice), in which RAS is activated selectively in late pregnancy, under deficient, normal or active Nrf2 conditions. The perinatal outcomes of PAH mice were analyzed and compared with the normal pregnant (NP) mice.

Results:

PAH mice with genetic deletion of Nrf2 rescued the maternal and fetal mortality, as well as intrauterine growth retardation (IUGR). The level of oxidative DNA damage in the placental labyrinth zone was inversely correlated with the level of Nrf2 activity. Formation of the placental vascular network was severely repressed by preeclampsia, and Nrf2 deficiency rescued the network formation with high ROS accumulation. Nrf2-hyperactivated placenta showed severely repressed angiogenesis with negligible oxidative DNA damages and the decrease of angiogenic chemokine expressions. Consistently, pharmacological induction of Nrf2 after 13.5 days post coitum exacerbated maternal mortality and IUGR.

Conclusions:

Our findings demonstrate that the inhibition of Nrf2 ameliorates perinatal outcomes in the RAS-induced preeclampsia model, and that ROS signaling is essential for placental angiogenesis in preeclampsia.

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