The effect of prenatal pravastatin treatment on altered fetal programming of postnatal growth and metabolic function in a preeclampsia-like murine model

McDonnold, Mollie; Tamayo, Esther; Kechichian, Talar; Gamble, Phyllis; Longo, Monica; Hankins, Gary D.V.; Saade, George R.; Costantine, Maged M.

doi:10.1016/j.ajog.2014.01.010

Cited by 35 publications

(26 citation statements)

References 37 publications

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“…Provocatively, the offspring of PE+PRAV mice were normotensive and did not show signs of metabolic disease like the offspring born to untreated PE mothers. In agreement with our observations that pravastatin treatment during pregnancy prevented metabolic disease in the offspring, a recent study has also shown that pravastatin treatment reversed abnormal glucose levels in the offspring in a mouse model of PE induced by systemic overexpression of sFlt-1 (46).…”

Section: Discussionsupporting

confidence: 81%

Pravastatin therapy during preeclampsia prevents long-term adverse health effects in mice

et al. 2018

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Section: Discussionsupporting

confidence: 81%

Pravastatin therapy during preeclampsia prevents long-term adverse health effects in mice

et al. 2018

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“…Statins have shown sex-specificity in outcomes following statin use for stroke and heart attack prevention [74]–[75]. Related study in this preeclampsia model has shown varying responses to pravastatin for both cardiovascular and metabolic parameters in offspring [76]–[77]. Future research should build on this growing literature of sex-specific effects and targeted therapy.…”

Section: Discussionmentioning

confidence: 88%

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

et al. 2014

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ObjectiveUsing an animal model, we have previously shown that preeclampsia results in long-term adverse neuromotor outcomes in the offspring, and this phenotype was prevented by antenatal treatment with pravastatin. This study aims to localize the altered neuromotor programming in this animal model and to evaluate the role of pravastatin in its prevention.Materials and MethodsFor the preeclampsia model, pregnant CD-1 mice were randomly allocated to injection of adenovirus carrying sFlt-1 or its control virus carrying mFc into the tail vein. Thereafter they received pravastatin (sFlt-1-pra “experimental group”) or water (sFlt-1 “positive control”) until weaning. The mFc group (“negative control”) received water. Offspring at 6 months of age were sacrificed, and whole brains underwent magnetic resonance imaging (MRI). MRIs were performed using an 11.7 Tesla vertical bore MRI scanner. T2 weighted images were acquired to evaluate the volumes of 28 regions of interest, including areas involved in adaptation and motor, spatial and sensory function. Cytochemistry and cell quantification was performed using neuron-specific Nissl stain. One-way ANOVA with multiple comparison testing was used for statistical analysis.ResultsCompared with control offspring, male sFlt-1 offspring have decreased volumes in the fimbria, periaquaductal gray, stria medullaris, and ventricles and increased volumes in the lateral globus pallidus and neocortex; however, female sFlt-1 offspring showed increased volumes in the ventricles, stria medullaris, and fasciculus retroflexus and decreased volumes in the inferior colliculus, thalamus, and lateral globus pallidus. Neuronal quantification via Nissl staining exhibited decreased cell counts in sFlt-1 offspring neocortex, more pronounced in males. Prenatal pravastatin treatment prevented these changes.ConclusionPreeclampsia alters brain development in sex-specific patterns, and prenatal pravastatin therapy prevents altered neuroanatomic programming in this animal model.

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“…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).…”

Section: Prevention Strategiesmentioning

confidence: 99%

A Dormant Microbial Component in the Development of Preeclampsia

Kell

Kenny

2016

Front. Med.

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Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “preeclampsia” that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.

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The effect of prenatal pravastatin treatment on altered fetal programming of postnatal growth and metabolic function in a preeclampsia-like murine model

Cited by 35 publications

References 37 publications

Pravastatin therapy during preeclampsia prevents long-term adverse health effects in mice

Pravastatin therapy during preeclampsia prevents long-term adverse health effects in mice

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

A Dormant Microbial Component in the Development of Preeclampsia

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