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

Carver, Alissa; Andrikopoulou, Maria; Lei, Jun; Tamayo, Esther; Gamble, Phyllis; Hou, Zhipeng; Zhang, Jiangyang; Mori, Susumu; Saade, George R.; Costantine, Maged M.; Burd, Irina

doi:10.1371/journal.pone.0100873

Cited by 31 publications

(24 citation statements)

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“…This is the first study examining the role of sFlt-1 on soft neurologic signs. Our data is in agreement with a mouse model of pre-eclampsia induced by pregnancy-specific overexpression of sFlt-1, where offspring displayed impairments in balance and coordination, and was prevented with maternal pravastatin treatment (Carver et al, 2014). These findings may transform our understanding of the pathophysiologic role of angiogenesis in altering the soft neurologic signs endophenotype, with the potential for novel therapeutic avenues.…”

Section: Discussionsupporting

confidence: 90%

“…Only a few studies have looked at the effects of angiogenesis on brain structure. A mouse model of pre-eclampsia with sFlt-1 overexpression demonstrated brain structural impairments in offspring, an effect that was attenuated with maternal pravastatin treatment (Carver et al, 2014). A similar study in humans, offspring of pre-eclamptic mothers with elevated sFlt-1 showed brain structural and vascular changes compared to controls (Ratsep et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Elevations in serum VEGF levels were associated with decreased PFC volume (Pillai et al, 2015). An animal model investigating offspring from pre-eclamptic mothers, demonstrated that elevated sFlt-1 had a reduction in brain volume that was prevented with prenatal pravastatin treatment (Carver et al, 2014). Taken together, these findings point to the importance of examining the role sFlt-1 on psychosis risk.…”

Section: Introductionmentioning

confidence: 99%

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Association of sFlt-1 and worsening psychopathology in relatives at high risk for psychosis: A longitudinal study

Lizano

Yao

Tandon

et al. 2017

Schizophrenia Research

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Background Angiogenic dysfunction and abnormalities in psychopathology and brain structure have been reported in schizophrenia, but their relationships are mostly unknown. We recently demonstrated that sFlt-1, anti-angiogenic factor, was significantly elevated in patients at familial high-risk for psychosis (FHR). We hypothesized that elevated sFlt-1 correlates with baseline and longitudinal changes in psychopathology, cognition, and brain structure. Methods Plasma sFlt-1 in FHR (n=35) and HC (n=39) was obtained at baseline. Schizotypal, cognitive, soft neurologic signs, and structural brain imaging (1.5T T1-weighted MRI, FreeSurfer software) measures were obtained in both groups. Longitudinal clinical and brain structural measures were obtained in a subgroup of FHR patients. Baseline data analysis used correlations between sFlt-1 and clinical/imaging measures and adjusted for multiple corrections. Linear mixed-effects models described differences in trajectories between high sFlt-1 and low sFlt-1. Results Baseline sFlt-1 was significantly correlated with soft neurologic signs (r=0.27, p=0.02) and right entorhinal volume (r=0.50, p=0.02), but not other baseline clinical/brain structural measures. Longitudinal examination of the FHR group (sFlt-1 high, n=14; sFlt-1 low, n=14) demonstrated that high sFlt-1 was significantly associated with worsening schizotypal symptoms (t=2.4, p=0.018). Reduced right hippocampal/parahippocampal volume/thickness trajectories were observed in high versus low sFlt-1 groups. Conclusions The findings from this FHR study demonstrate that peripheral markers of angiogenic dysfunction can predict longitudinal clinical and brain structural changes. Also, these findings further support the hypothesis of altered microvascular circulation in schizophrenia and those at risk.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of sFlt-1 and worsening psychopathology in relatives at high risk for psychosis: A longitudinal study

Lizano

Yao

Tandon

et al. 2017

Schizophrenia Research

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“…2,3 Interestingly, pre-eclampsia and other pregnancy complications have been associated with an increased risk for schizophrenia in adults, and can have additive effects to genetic factors (Dalman et al , 1999, 2001; Cannon et al , 2000). Additionally, it was demonstrated using an animal model that offspring from pre-eclamptic mothers with adenoviral elevated sFlt-1, had a sex-specific reduction in brain volume that was prevented with prenatal pravastatin treatment (Carver et al , 2014). When taken together, this evidence supports a model for genetic vulnerability and obstetrical complication having an additive effect that may result in the development of psychosis.…”

Section: Discussionmentioning

confidence: 99%

Angiogenic and immune signatures in plasma of young relatives at familial high-risk for psychosis and first-episode patients: A preliminary study

Lizano

Keshavan

Tandon

et al. 2016

Schizophrenia Research

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Schizophrenia (SZ) is a heterogeneous disorder that presents in adolescence, persists into adulthood, and has many clinical features. Recent evidence suggests that abnormalities in inflammatory, neurotrophic, and angiogenic processes may play a role in the etiology of SZ. The identification of molecular biomarkers early in the course of disease is crucial to transforming diagnostic and therapeutic avenues. We investigated 14 molecular analytes focusing on inflammatory, neurotrophic and angiogenic pathways from the plasma of antipsychotic-naïve familial high risk for SZ (FHR; n=35) and first-episode psychosis (FEP; n=45) subjects, in comparison to healthy controls (HC, n=39). We identified distinct alterations in molecular signatures in young relatives at FHR for SZ prior to psychosis onset and FEP subjects. Firstly, the expression of soluble fms-like tyrosine kinase (sFlt-1), an anti-angiogenic factor that binds vascular endothelial growth factor (VEGF), was significantly increased in the FHR group compared to HC, but not in FEP. Secondly, interferon gamma (IFNγ) was significantly reduced in the FEP group compared to HC. Thirdly, network analysis revealed a positive correlation between sFlt-1 and VEGF, suggesting an activation of the angiogenic cascade in the FHR group, which persists in FEP. Our results indicate an angiogenesis and immunological dysfunction early in the course of disease, shifting the balance towards anti-angiogenesis and inflammation.

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

Cited by 31 publications

References 82 publications

Association of sFlt-1 and worsening psychopathology in relatives at high risk for psychosis: A longitudinal study

Association of sFlt-1 and worsening psychopathology in relatives at high risk for psychosis: A longitudinal study

Angiogenic and immune signatures in plasma of young relatives at familial high-risk for psychosis and first-episode patients: A preliminary study

A Dormant Microbial Component in the Development of Preeclampsia

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