Abstract
Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1), and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Progesterone induced blocking factor (PIBF) is a product of progesterone signaling that blocks inflammatory processes and we have previously shown PIBF to lower mean arterial blood pressure (MAP) and sFlt-1 in a rat model of PE. Infusion of sFlt-1 causes hypertension and many characteristics of PE in pregnant rodents, however, its role in causing mt dysfunction is unknown. Therefore, we hypothesize that PIBF will improve mt function and MAP in response to elevated sFlt-1 during pregnancy. We tested our hypothesis by infusing sFlt-1 via miniosmotic pumps in normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg−1·day−1) on gestation days (GD) 13–19 in the presence or absence of PIBF (2.0 µg/mL) injected intraperitoneally on GD 15 and examined mean arterial blood pressure (MAP) and placental mt ROS on GD 19. sFlt-1 increased MAP to 112 + 2 (n = 11) compared to NP rats (98 + 2 mmHg, n = 15, p < 0.05), which was lowered in the presence of sFlt-1 (100 + 1 mmHg, n = 5, p < 0.05). Placental mtATP was reduced in sFlt-1 infused rats versus NP controls, but was improved with PIBF. Placental mtROS was elevated with sFlt-1 compared to NP controls, but was reduced with PIBF. Sera from NP + sFlt-1 increased endothelial cell mtROS, which was attenuated with PIBF. These data demonstrate sFlt-1 induced HTN during pregnancy reduces placental mt function. Importantly, PIBF improved placental mt function and HTN, indicating the efficacy of improved progesterone signaling as potential therapeutics for PE.
Highlights
Preeclampsia (PE) is defined as new onset hypertension during pregnancy after the 20th week of gestation
Placental mitochondrial state 3 respiration was lower in normal pregnant (NP) + soluble fms-like tyrosine kinase-1 (sFlt-1) infused rats (191 ± 54 pmol of O2/s/mg, n = 5) compared to NP controls
Uncoupled respiration decreased in NP + sFlt-1 infused rats (96 ± 34 pmol of O2/s/mg, n = 5) compared to NP controls
Summary
Preeclampsia (PE) is defined as new onset hypertension during pregnancy after the 20th week of gestation. It is associated with or without chronic immune activation, proteinuria, fetal growth restriction, and maternal endothelial dysfunction [1]. PE is a major cause of maternal, fetal, and neonatal morbidity and mortality affecting 5–7% of pregnancies worldwide [2]. The fetus is at risk for intrauterine growth restriction, prematurity, and intrauterine death [3]. Despite being a leading cause of maternal death and maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of PE are unclear. Additional investigation into the pathophysiological mechanisms resulting in the development of PE is needed in order to elucidate potential therapies
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