Preeclampsia is a hypertensive disorder of pregnancy with consequences extending beyond the perinatal period for the mother and the offspring. Women a history of preeclampsia are more likely to self-report cognitive complaints and have impaired attention, learning, and memory, suggesting an association between pregnancies with preeclampsia and maternal cognitive function. Recent large cohort studies showed that preeclampsia was associated with increased risk of dementia, particularly vascular dementia, since women with a history of preeclampsia had more than a 3-fold increased risk of vascular dementia compared with women with no history of preeclampsia. It is unknown whether dysfunction of the maternal peripheral vasculature, which is a hallmark of preeclampsia, extends to dysfunction in arteries supplying the brain and whether preeclampsia causes early signs of neurodegeneration in the maternal brain increasing risk of maternal cognitive impairment. The proposed studies will investigate the role of placental ischemia (common feature of pregnancies with preeclampsia) and increased Toll-like receptor-9 activity (TLR-9; documented in women with preeclampsia) in the development of preclinical stages of maternal dementia. We hypothesize that placental ischemia induces preclinical stages of maternal dementia through activation of TLR-9 signaling and this impairment persist postpartum. Aim 1 will determine the effects of a placental ischemia on maternal cognitive function during pregnancy and postpartum. Hypothesis: Placental ischemia impairs maternal cognitive function and this impairment persists postpartum. To test this hypothesis, we will measure maternal hippocampal-dependent cognitive behavior and short-term contextual and episodic memory at the end of gestation and two months postpartum in an experimental model of preeclampsia with placental ischemia. Aim 2 will determine the contribution of TLR-9 activation to brain neurodegeneration in an experimental model of preeclampsia with placental ischemia. Hypothesis: Placental ischemia induces maternal brain inflammation and oxidative stress through activation of TLR-9 signaling. To test this hypothesis, we will measure oxidative stress and cytokine expression in maternal brain regions implicated in pre-clinical stages of neurodegenerative diseases in rats with experimental preeclampsia with placental ischemia. Pregnant rats will be treated with vehicle or a TLR-9 inhibitor. Aim 3 will determine the contribution of TLR-9 activation to vascular impairment in arteries supplying the maternal brain in an experimental model of preeclampsia with placental ischemia. Hypothesis: Carotid arteries from rats with experimental preeclampsia have increased stiffness, increased generation of reactive oxygen species (ROS) and enhanced vasoconstrictor responses and these effects are mediated by activation of TLR-9 signaling. To test this hypothesis, we will use carotid arteries from rats used for Aim 2. Successful completion of the proposed studies will establish the contribution of TLR-9 stimulation induced by placental ischemia during pregnancy to preclinical stages of maternal cognitive impairment.
|Effective start/end date||1/01/21 → 31/12/21|
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