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.