Maternal Hypertension and Offspring Cardiometabolic Disease Risk is Attenuated after Weight Loss in Obese Preeclamptic‐like BPH/5 Female Mice

Abstract

Preeclampsia (PE) is a life‐threatening disorder of pregnancy that presents as late gestational hypertension and at least one other sign/symptom, such as proteinuria. It occurs in ~10% of pregnant women worldwide and the cause is unknown. Pre‐existing maternal hypertension and obesity has been associated with adverse outcomes, including PE and fetal growth restriction (FGR). To better understand the relationship of maternal PE risk (hypertension/obesity) and outcomes, we utilized the hyperphagic obese hypertensive BPH/5 mouse model of superimposed PE. We hypothesized that monitored food intake, via pair‐feeding the amount of normal chow consumed by age‐ and gestation‐matched lean normotensive C57 to BPH/5 mice, would attenuate maternal and offspring PE adverse outcomes.We have shown that adult BPH/5 female mice have an adverse cardiometabolic phenotype, hypertension, obesity with increased white adipose tissue (WAT), and dyslipidemia that is exaggerated by pregnancy. To test our hypothesis, BPH/5 and C57 females were instrumented with carotid catheters for radiotelemetric blood pressure monitoring prior to pregnancy. As previously described, pair‐feeding (PF) non‐pregnant BPH/5 female mice decreases body weight and WAT mass. When PF was performed for 10 days, we found a decrease in mean arterial pressure in BPH/5 PF versus ad libitum (AL) fed females (PF:121±2.8 vs AL:133±6 mmHg; n=3; p<0.05). When PF was performed in BPH/5 beginning at copulatory plug detection, embryonic day (e) 0.5, they failed to show a late‐gestational blood pressure rise from baseline (n=3; p>0.05) and attenuated proteinuria (PF: 84±15 vs AL: 177±16.5mg/dL; n=5; p<0.05). The PF paradigm increased median BPH/5 litter size (PF: 7, max‐min: 3‐8 vs AL:3, max‐min: 1‐6; n=26; p<0.05) and improved symmetrical FGR at e18.5 as assessed by fetal liver: body weight (PF: 13.63±0.7 vs AL:10.51±1.3; n=10; p<0.05).As BPH/5 female offspring age, they exhibit excessive catch‐up growth with FGR at birth and obesity with hyperleptinemia by adulthood (8 weeks) unlike male littermates. Adult female BPH/5 have cardiomegaly, hypertension, and bradycardia (n=7; p<0.05). Furthermore, adult female BPH/5 have hepatomegaly with microvesicular steatosis (p<0.05, n=3‐9). Importantly, adult BPH/5 female offspring born to PF BPH/5 mothers do not display these cardiometabolic risk factors: obesity (PF: 18±1.8 vs AL: 21±0.3g; n=16; p<0.05), hyperleptinemia (PF: 5.5±0.8 vs AL: 12.6±3.1ng/mL; n=6; p<0.05), hepatomegaly (PF: 1178±27 vs AL: 1475±69mg; n=16; p<0.05), and cardiomegaly (PF: 135.1±5.1 vs AL: 166.8±12.8mg; n=6; p<0.05) with age. Further investigations are necessary to understand the mechanism whereby maternal hyperphagia prevention and weight loss in BPH/5 improves offspring cardiometabolic disease as they age in a sex‐dependent manner. Finally, we seek to determine if interventions during pregnancy not only improve maternal cardiometabolic health, but also that of subsequent generations through augmented fetal programming during PE.