Abstract
Simple SummaryPreeclampsia is a life-threatening disorder that occurs in 10% of pregnant women worldwide. It presents as high blood pressure and multi-organ damage that when left untreated can result in death to both mother and baby. Treatment involves delivery of the placenta as well as the baby, often prematurely. Unfortunately, the cause of preeclampsia is unknown. However, there are known risk factors in women that may contribute to preeclampsia, including obesity. Increased adipose tissue (fat) has the potential to promote inflammation during pregnancy, which may negatively impact development of the baby and placenta, and lead to preeclampsia. This study aimed to show that reversal of maternal obesity through diet lowers inflammation in the fat and improves placental development, both of which have been shown to be necessary for pregnancy success. Utilizing obese female mice that demonstrate signs of preeclampsia (BPH/5), we showed that calorie restriction lowered inflammatory immune factors (complement) in the fat and restored essential growth factors in the developing placenta. In conclusion, these data suggest that targeting maternal obesity using calorie restriction and weight loss may improve pregnancy outcomes. Further studies are necessary to determine the influence of fat reduction in women and their likelihood of developing preeclampsia.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.
Highlights
One in every three women of reproductive age (15–49 years) in the US has obesity;a risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertension, macrosomia, and preeclampsia (PE) [1] PE is a serious disorder of pregnancy characterized by high blood pressure and multiorgan dysfunction during the second half of gestation [2,3,4]
Complement Factor 3 mRNA is Upregulated in the Reproductive white adipose tissue (WAT) of blood pressure high (BPH)/5 Females Prior to Complement Factor 3 mRNA is Upregulated in the Reproductive WAT of BPH/5 Females Prior to
We previously showed that CR via pair feeding reduces body weight and visceral mass, and lowers TNFα and interleukin (IL)-6 mRNA in BPH/5 female reproductive WAT [17]
Summary
One in every three women of reproductive age (15–49 years) in the US has obesity;a risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertension, macrosomia, and preeclampsia (PE) [1] PE is a serious disorder of pregnancy characterized by high blood pressure and multiorgan dysfunction during the second half of gestation [2,3,4]. The etiology remains unknown, delivery of both the baby and placenta is often necessary to prevent fetal and maternal morbidity and mortality [1]. Successful placental development depends on several tightly regulated physiological processes, including implantation, decidualization, and angiogenesis [2]. PE is associated with inadequate trophoblast invasion and remodeling of spiral arteries as a result of angiogenic, immune, and inflammatory dysregulation at the maternal–fetal interface [3,5]. This, along with increased activation of the complement system, is associated with a systemic and placental angiogenic imbalance in preeclamptic women and rodent models of PE [7]. The complement system was previously indicated to be a key regulator of the maternal immune response during pregnancy. Failure of the complement system to properly mediate the clearance of waste and debris created during placentation may contribute to the pathogenesis of PE [8]
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