Adverse metabolic phenotype of female offspring exposed to preeclampsia in utero: a characterization of the BPH/5 mouse in postnatal life

Sutton, Elizabeth F.; Lob, Heinrich E.; Song, Jiunn; Xia, Youyi; Butler, Scott D.; Liu, Chin‐Chi; Redman, Leanne M.; Sones, Jenny L.

doi:10.1152/ajpregu.00512.2016

Cited by 31 publications

(80 citation statements)

References 33 publications

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“…Ongoing investigations seek to identify the cell types contributing to aberrant gene expression in the BPH/5 decidua. Further, recently published data from the Sones laboratory demonstrated that BPH/5 female mice have an adverse metabolic phenotype from early adulthood, which includes hyperphagia and obesity with increased white adipose tissue (WAT), proinflammatory reproductive WAT, and leptin resistance (63). Obesity before and at the time of conception has been linked to adverse pregnancy outcomes (64, 65).…”

Section: Discussionmentioning

confidence: 99%

Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia

et al. 2018

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Preeclampsia (PE), a hypertensive disorder of pregnancy, is a leading cause of maternal and fetal morbidity and mortality. Although the etiology is unknown, PE is thought to be caused by defective implantation and decidualization in pregnancy. Pregnant blood pressure high (BPH)/5 mice spontaneously develop placentopathies and maternal features of human PE. We hypothesized that BPH/5 implantation sites have transcriptomic alterations. Next-generation RNA sequencing of implantation sites at peak decidualization, embryonic day (E)7.5, revealed complement gene up-regulation in BPH/5 vs. controls. In BPH/5, expression of complement factor 3 was increased around the decidual vasculature of E7.5 implantation sites and in the trophoblast giant cell layer of E10.5 placentae. Altered expression of VEGF pathway genes in E5.5 BPH/5 implantation sites preceded complement dysregulation, which correlated with abnormal vasculature and increased placental growth factor mRNA and VEGF expression at E7.5. By E10.5, proangiogenic genes were down-regulated, whereas antiangiogenic sFlt-1 was up-regulated in BPH/5 placentae. We found that early local misexpression of VEGF genes and abnormal decidual vasculature preceded sFlt-1 overexpression and increased complement deposition in BPH/5 placentae. Our findings suggest that abnormal decidual angiogenesis precedes complement activation, which in turn contributes to the aberrant trophoblast invasion and poor placentation that underlie PE.-Sones, J. L., Merriam, A. A., Seffens, A., Brown-Grant, D.-A., Butler, S. D., Zhao, A. M., Xu, X., Shawber, C. J., Grenier, J. K., Douglas, N. C. Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia.

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Section: Discussionmentioning

confidence: 99%

Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia

et al. 2018

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“…Continued studies by this group evaluated the transcriptome at E7.5 implantation sites and E10.5 placenta demonstrating significant upregulation of C3 gene expression and reinforcing the importance of the complement system in the placental pathology [50]. The most recent study from this group [51] characterized the metabolic phenotype of offspring of the BPH/5 mouse and demonstrated the long-term consequences that accompany the adverse complement activation early in pregnancy.…”

Section: The Complement System In Stage 1 Of Placental Preeclampsiamentioning

confidence: 99%

The Complement System and Preeclampsia

2017

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Purpose of review Preeclampsia affects 3–4% of pregnancies with few treatment options to reduce maternal and fetal harm. Recent evidence that targeting the complement system may be an effective therapeutic strategy in prevention or treatment of preeclampsia will be reviewed. Recent findings Studies in humans confirm the safety and efficacy of C5 blockade in complement-mediated disorders of pregnancy, including preeclampsia. Animal models mimic the placental abnormalities, and/or the maternal symptoms, which characterize preeclampsia. These models in mouse and rat have defined a role for complement and its regulators in placental dysfunction, hypertension, proteinuria, endothelial dysfunction, fetal growth restriction and angiogenic imbalance, thus informing future human studies. Summary Targeting excessive complement activation, particularly the terminal complement complex (C5b-9) and C5a may be an effective strategy to prolong pregnancy in women with preeclampsia. Continued research is needed to identify the initiator(s) of activation, the pathways involved and the key component(s) in the pathophysiology to allow development of safe and effective therapeutics to target complement without compromising its role in homeostasis and host defense.

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“…Throughout all experiments, mice were fed ad libitum standard 5001 chow. Pair-feeding of nonpregnant BPH/5 female mice was done as previously described [17] by feeding the same amount of normal chow to BPH/5 as consumed by age-matched C57 female mice for 2 weeks. Intrastrain timed matings with day of vaginal plug detection denoted as e0.5 were performed with BPH/5 pair-feeding, beginning at e0.5 and continuing for 7 days until the mice were sacrificed, as previously described [14].…”

Section: Animalsmentioning

confidence: 99%

Complement in Reproductive White Adipose Tissue Characterizes the Obese Preeclamptic-Like BPH/5 Mouse Prior to and During Pregnancy

Olson

Reijnders

Gomes

et al. 2020

Biology

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Preeclampsia (PE) is a serious hypertensive disorder of pregnancy characterized by abnormal placental development with an unknown etiology. To better understand which women will develop PE, a number of maternal risk factors have been identified, including obesity. Visceral white adipose tissue (WAT) contains inflammatory mediators that may contribute to PE. To explore this, we utilized the blood pressure high (BPH)/5 mouse model of superimposed PE that spontaneously recapitulates the maternal PE syndrome. We hypothesized that BPH/5 visceral WAT adjacent to the female reproductive tract (reproductive WAT) is a source of complement factors that contribute to the inflammatory milieu and angiogenic imbalance at the maternal–fetal interface in this model and in preeclamptic women. To test our hypothesis, we calorie-restricted BPH/5 females for two weeks prior to pregnancy and the first seven days of pregnancy, which attenuated complement component 3 (C3) but not complement factor B, nor complement factor D, (adipsin) in the reproductive WAT or the implantation site in BPH/5. Furthermore, calorie restriction during pregnancy restored vascular endothelial and placental growth factor mRNA levels in the BPH/5 implantation site. These data show maternal reproductive WAT may be a source of increased C3 during pregnancy, which is increased at the maternal–fetal interface in preeclamptic BPH/5 mice. It also suggests that calorie restriction could regulate inflammatory mediators thought to contribute to placental dysfunction in PE. Future studies are necessary to examine the effect of calorie restriction on C3 throughout pregnancy and the role of maternal obesity in PE.

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Adverse metabolic phenotype of female offspring exposed to preeclampsia in utero: a characterization of the BPH/5 mouse in postnatal life

Cited by 31 publications

References 33 publications

Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia

Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia

The Complement System and Preeclampsia

Complement in Reproductive White Adipose Tissue Characterizes the Obese Preeclamptic-Like BPH/5 Mouse Prior to and During Pregnancy

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