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

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. © FASEB.

Citation

Jenny L Sones, Kalie F Beckers, Morgan Alston, Brianna L Rogers, Daniella L Adams, Chin-Chi Liu. Maternal Hypertension and Offspring Cardiometabolic Disease Risk is Attenuated after Weight Loss in Obese Preeclamptic-like BPH/5 Female Mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022 May;36 Suppl 1

PMID: 35554721

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