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

Abstract

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.

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

“…We previously showed that adult, nonpregnant BPH/5 female mice exhibit increased body weight and proinflammatory reproductive WAT (i.e., TNF-α) compared to controls [17], which persists in early pregnancy (e7.5) [14]. At that time, the maternal-fetal interface in BPH/5 mice is characterized by an overexpression of inflammatory mediators, including C3 and CfB but not C1qa, which is associated with an angiogenic imbalance [7]. We hypothesized that increased reproductive WAT could be a source of complement factors and, if reduced by maternal weight loss, would improve the angiogenic imbalance in BPH/5 implantation sites at e7.5, the peak of decidualization prior to placenta formation.…”

“…An angiogenic imbalance in early pregnancy characterizes BPH/5 mice and other models of PE [1,7]. Complement inhibition was shown to restore placental VEGF levels in BPH/5 placenta [15].…”

“…BPH/5 females are hyperphagic and subsequently show increased adiposity, including increased reproductive visceral white adipose tissue (WAT) deposition adjacent to the reproductive tract before and during pregnancy [14]. Recently, Sones et al demonstrated that expression of VEGF and PlGF, as well as CfB and C3, are upregulated at the maternal-fetal interface of BPH/5 mice at the peak of decidualization in murine pregnancy at embryonic day (e) 7.5 [7]. However, expression of complement C1q subcomponent subunit A (C1qa) was similar in BPH/5 and controls.…”

Deletion of Prl7d1 causes placental defects at mid‐pregnancy in mice

“…In addition, the placenta itself also synthesizes a variety of hormones, enzymes, and cytokines, which are mostly encoded by placenta‐specific genes, to adjust placental physiology and mediate gas exchange, nutrient uptake, and waste elimination between the mother and fetus (Bu, Alam, Dhakal, Vivian, & Soares, ; Burton & Fowden, ; Naruse et al, ; Simmons, Rawn, Davies, Hughes, & Cross, ). Emerging evidence suggests that some internal or external factors can target certain placenta‐specific genes, and therefore may impair placenta formation and function, ultimately contributing to the etiology of many pregnancy‐related diseases such as pre‐eclampsia, intrauterine growth restriction, and abortion; this can have consequences for the long‐term health of the individual (Huynh, Dawson, Roberts, & Bentley‐Lewis, ; Kenchegowda, Natale, Lemus, Natale, & Fisher, ; Sones et al, ). Thus, decoding the functions of these placental genes will help to elucidate placental physiology and pregnancy‐related diseases.…”

“…the long-term health of the individual (Huynh, Dawson, Roberts, & Bentley-Lewis, 2015;Kenchegowda, Natale, Lemus, Natale, & Fisher, 2017;Sones et al, 2018). Thus, decoding the functions of these placental genes will help to elucidate placental physiology and pregnancy-related diseases.…”