Dyslipidemia and the role of adipose tissue in early pregnancy in the BPH/5 mouse model for preeclampsia

Abstract

The hypertensive pregnancy disorder preeclampsia (PE) is a leading cause of fetal and maternal morbidity/mortality. Obesity increases the risk to develop PE, presumably via the release of inflammatory mediators from the adipose tissue, but the exact etiology remains largely unknown. Using obese PE-like blood pressure high subline 5 (BPH/5) and lean gestational age-matched C57Bl6 mice, we aimed to obtain insight into differential reproductive white adipose tissue (rWAT) gene expression, circulating lipids and inflammation at the maternal-fetal interface during early pregnancy. In addition, we investigated the effect of 7 days 25% calorie restriction (CR) in early pregnancy on gene expression in rWAT and implantation sites. Compared with C57Bl6, female BPH/5 are dyslipidemic before pregnancy and show an amplification of rWAT mass, circulating cholesterol, free fatty acids, and triacylglycerol levels throughout pregnancy. RNA sequencing showed that pregnant BPH/5 mice have elevated gene enrichment in pathways related to inflammation and cholesterol biosynthesis at embryonic day ( e) 7.5. Expression of cholesterol-related HMGCS1, MVD, Cyp51a1, and DHCR was validated by quantitative reverse-transcription-polymerase chain reaction. CR during the first 7 days of pregnancy restored the relative mRNA expression of these genes to a level comparable to C57Bl6 pregnant females and reduced the expression of circulating leptin and proinflammatory prostaglandin synthase 2 in both rWAT and implantation sites in BPH/5 mice at e7.5. Our data suggest a possible role for rWAT in the dyslipidemic state and inflammatory uterine milieu that might underlie the pathogenesis of PE. Future studies should further address the physiological functioning of the adipose tissue in relation to PE-related pregnancy outcomes.

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

“…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]. Reproductive WAT and implantation sites (uterus and embryo) were collected and flash frozen from ad libitum-fed and pair-fed, nonpregnant and pregnant BPH/5 and C57 female mice.…”

“…Total RNA was isolated from reproductive WAT of BPH/5 and C57 mice prior to pregnancy, as well as reproductive WAT and implantation sites at e7.5. Tissue homogenization and cDNA synthesis were performed as previously described [14]. qRT-PCR was used to determine the amount of C3 (region corresponding to the alpha chain), CfB, adipsin, VEGF, and PlGF mRNA (Table S1), with 25 ng cDNA per reaction in triplicate using SYBR green.…”

“…To investigate this phenomenon, we utilized the preeclamptic-like blood pressure high (BPH)/5 mouse model [2,13], which is used for studying pre-pregnancy and early pregnancy events that may contribute to PE, as BPH/5 spontaneously develops the cardinal maternal signs (late gestational hypertension and proteinuria) beginning at day 14 of pregnancy, which resolve upon delivery of pups and placentae [2,13]. 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].…”

The role of DRAM1 in mitophagy contributes to preeclampsia regulation in mice

“…Dyslipidemia is closely related to the occurrence and development of PE during pregnancy [1]. We measured triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), and high density lipoprotein (HDL) levels on E19.5.…”

“…Preeclampsia (PE) is characterized by hypertension with or without proteinuria after the 20th week of pregnancy and is associated with endothelial dysfunction, oxidative stress, systemic vasoconstriction, inflammation, intrauterine growth restriction, and multiorgan dysfunction [1,2]. The World Health Organization reports that more than 60,000 pregnant women worldwide die of eclampsia each year [3].…”