OS 05-05 Nrf2 DEFICIENCY ALLEVIATES PERINATAL COMPLICATIONS IN PREGNANCY-ASSOCIATED HYPERTENSION MICE VIA ENHANCING PLACENTAL ANGIOGENESIS.
نویسندگان
چکیده
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.
منابع مشابه
Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes.
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...
متن کاملHypopituitarism and successful pregnancy.
Hypopituitarism is a disorder characterized by the deficiency of one or more of the hormones secreted by the pituitary gland. Hypopituitarism patients may present the symptoms of amenorrhea, poor pregnancy potential, infertility, and no production of milk after delivery. Successful pregnancy in hypopituitarism patient is rare because hypopituitarism is associated with an increased risk of pregn...
متن کاملThe SK3 channel promotes placental vascularization by enhancing secretion of angiogenic factors.
Proper placental perfusion is essential for fetal exchange of oxygen, nutrients, and waste with the maternal circulation. Impairment of uteroplacental vascular function can lead to pregnancy complications, including preeclampsia and intrauterine growth restriction (IUGR). Potassium channels have been recognized as regulators of vascular proliferation, angiogenesis, and secretion of vasoactive f...
متن کاملPregnancy/Preeclampsia A Critical Role of Interleukin-10 in Modulating Hypoxia-Induced Preeclampsia-Like Disease in Mice
Hypoxia has been implicated in the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy. However, in vivo evidence and mechanistic understanding remain elusive. Preeclampsia is associated with impaired placental angiogenesis. We have recently shown that interleukin (IL)-10 can support trophoblast-driven endovascular crosstalk. Accordingly, we hypothesize that pathological levels o...
متن کاملA critical role of interleukin-10 in modulating hypoxia-induced preeclampsia-like disease in mice.
Hypoxia has been implicated in the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy. However, in vivo evidence and mechanistic understanding remain elusive. Preeclampsia is associated with impaired placental angiogenesis. We have recently shown that interleukin (IL)-10 can support trophoblast-driven endovascular crosstalk. Accordingly, we hypothesize that pathological levels o...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Journal of hypertension
دوره 34 Suppl 1 شماره
صفحات -
تاریخ انتشار 2016