AT1-AA inhibition during pregnancy does not impact offspring outcomes in a rat model of preeclampsia

Preeclampsia (PE), new onset hypertension with end-organ damage in pregnancy, is associated with maternal death and morbidity, increased uterine artery resistance (UARI), low birth weight, and B cells producing agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). AT1-AA is produced during pregnancy, postpartum, and is in fetal circulation of PE women. The Reduced Uterine Perfusion Pressure (RUPP) rat model of PE exhibits these features and we have shown that administration of a seven amino acid sequence peptide (7AA), which blocks the actions of AT1-AA, improves PE features in the RUPP rat. However, 7AA’s effect on the long-term health of RUPP rat offspring is unknown. We hypothesize that 7AA will not worsen outcomes for offspring born to the RUPP rat model of PE. To test our hypothesis, 7AA (24 ug/day) was given on gestation day 14 via mini-osmotic pumps to control and RUPP dams. UARI was measured using Doppler ultrasound, pup weights were recorded within 12 hours of birth. Mean arterial pressure (MAP) was measured and whole blood was collected to measure immune cells by flow cytometry at 16 weeks. A two-way ANOVA was used for statistical analysis. UARI was increased in RUPP (0.70±0.02,n=10,p< 0.05) compared to controls (0.47±0.02,n=8) and improved with 7AA (0.49±0.02,n=10,p< 0.05). There was no significant change in offspring birth weight of RUPPs (6.0±0.21g,n=8) with or without 7AA (5.5±0.08g,n=7). At age 16 weeks there were no changes in weight (381±9g n=8 vs 374±12g n=6), MAP (138±4 vs 122±9mmHg), circulating B cells (8±4.2% vs 9±7.6%), or cytolytic NK cells (9±3.6% vs 2±1.1%) in male RUPP offspring with or without perinatal 7AA. There were no changes in weight (234±2g,n=7 vs 236±7g,n=5), MAP (123±7vs 132±10mmHg), circulating B cells (5±1.7% vs 4±2.2%), or NK cells (48±15.3% vs 22±15.5%) in female offspring of RUPP rats with or without 7AA. Our findings indicate that perinatal 7AA improves maternal PE features without negatively impacting fetal outcomes indicating promising potential to treat PE.