Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes.

Published online

Journal Article

Placental activation of the renin-angiotensin system (RAS) plays a key role in the pathogenesis of preeclampsia. Reactive oxygen species (ROS) are thought to affect placental angiogenesis, which is critical for preventing preeclampsia pathology. We examined the role of ROS in preeclampsia by genetically modifying the Keap1-Nrf2 pathway, a cellular antioxidant defense system, in a mouse model of RAS-induced preeclampsia. Nrf2 deficiency would be expected to impair cellular antioxidant responses; however, Nrf2 deficiency in preeclamptic mice improved maternal and fetal survival, ameliorated intra-uterine growth retardation, and augmented oxidative DNA damage. Furthermore, the placentas of Nrf2-deficient mice had increased endothelial cell proliferation with dense vascular networks. In contrast, the placentas of preeclamptic mice with overactive Nrf2 showed repressed angiogenesis, which was associated with decreased expression of genes encoding angiogenic chemokines and cytokines. Our findings support the notion that ROS-mediated signaling is essential for maintaining placental angiogenesis in preeclampsia and may provide mechanistic insight into the negative results of clinical trials for antioxidants in preeclampsia.

Full Text

Duke Authors

Cited Authors

  • Nezu, M; Souma, T; Yu, L; Sekine, H; Takahashi, N; Wei, AZ-S; Ito, S; Fukamizu, A; Zsengeller, ZK; Nakamura, T; Hozawa, A; Karumanchi, SA; Suzuki, N; Yamamoto, M

Published Date

  • May 16, 2017

Published In

Volume / Issue

  • 10 / 479

PubMed ID

  • 28512147

Pubmed Central ID

  • 28512147

Electronic International Standard Serial Number (EISSN)

  • 1937-9145

Digital Object Identifier (DOI)

  • 10.1126/scisignal.aam5711

Language

  • eng

Conference Location

  • United States