The effect of maternal pravastatin therapy on adverse sensorimotor outcomes of the offspring in a murine model of preeclampsia

Abstract

Animal and human studies show that in-utero exposure to preeclampsia alters fetal programming and results in long-term adverse cardiovascular outcomes in the offspring. Human epidemiologic data also suggest that offspring born to preeclamptic mothers are also at risk of adverse long term neurodevelopmental outcomes. Pravastatin, a hydrophilic lipid-lowering drug with pleiotropic properties, was found to prevent the altered cardiovascular phenotype of preeclampsia and restore fetal growth in animal models, providing biological plausibility for its use as a preventive agent for preeclampsia. In this study, we used a murine model of preeclampsia based on adenovirus over-expression of the anti-angiogenic factor soluble Fms-like tyrosine kinase 1, and demonstrated that adult offspring born to preeclamptic dams perform poorly on assays testing vestibular function, balance, and coordination, and that prenatal pravastatin treatment prevents impairment of fetal programming.

Maternal Pravastatin Prevents Altered Fetal Brain Development in a Preeclamptic CD-1 Mouse Model

“…Those which demonstrated significant changes between treatment groups are described in Table 2. We have previously reported that adult offspring of “preeclamptic” mice display impaired performance on neuromotor testing of vestibular function, balance, and locomotor coordination in gender-specific patterns [8]. Additionally, expression of genes involved in neuronal migration, myelination, apoptosis and oxidative stress in the hypothalamus and frontal cortex were altered in these offspring (unpublished data).…”

“…However, this is balanced by consistency across this model in phenotypic and mRNA expression patterns (unpublished data) [8] as well as support of existing epidemiologic data [9]–[14]. Fourth, in this work, we examined offspring brains at a single time-point of 6 months, which was designed to evaluate long-term adulthood outcomes.…”

“…Overexpressing sFlt-1 in the murine model leads to hypertension, altered vascular and endothelial responses, and other manifestations of preeclampsia [5]–[6]. In addition, we showed that pups born to “preeclamptic” dams are more susceptible to hypoxic ischemic injury, have altered candidate gene expression in the brain, and as adults perform worse on neuromotor assays testing vestibular function, balance, and locomotor coordination compared with pups born to control mothers, all in a gender-specific manner [7]–[8]. These findings are in accordance with various epidemiologic studies showing altered neuromotor fetal programming in infants born to preeclamptic mothers [9]–[14].…”

“…Additionally, we demonstrated that prenatal treatment of these mice with pravastatin prevented fetal programming of abnormal neuromotor function and gene expression in the offspring. Specifically it restored performance on assays testing vestibular function, balance, and locomotor coordination as well as expression of genes involved in neuronal migration, myelination, apoptosis and oxidative stress to levels similar to control (unpublished data) [8]. The objectives of this study were to localize regions of the brain that are associated with preeclampsia's fetal programming of long-term neuromotor abnormalities and to determine the effect of maternal therapy with pravastatin in these regions.…”

A Dormant Microbial Component in the Development of Preeclampsia

“…In consequence, a number of authors have indicated the potential utility of statins in treating PE (113, 545, 1203–1213), and pravastatin has been the subject of a number of favorable studies (545, 1204, 1206, 1209, 1211, 1214, 1215), including in humans (1204, 1216–1218). Pravastatin seems more than ripe for a proper, randomized clinical trial (1203).…”