Perinatal Exposure to AT1-AA Induced Hypertension Causes Hypertension in First Generation Pregnant Female Offspring

Preeclampsia (PE), new-onset hypertension during pregnancy in association with organ dysfunction in addition to the placenta. PE is associated with chronic inflammation and fetal growth restriction (FGR) which is further associated with increased risk for hypertension and cardiovascular disease in adult offspring. Moreover, female PE children are at elevated risk for PE during pregnancy indicating a familial connection with PE. Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA) are produced in PE women, induce a PE phenotype when infused into pregnant rats, and are present in maternal circulation up to eight years postpartum. However, the role of AT1-AA in the risk for cardiovascular disease and PE in offspring of PE pregnancies is unknown. We have previously shown that perinatal exposure to AT1-AA during pregnancy causes adult female first generation (F1) offspring to have elevated blood pressure, therefore, the objective of this study was to determine if these adult female offspring exhibit hypertension during pregnancy. Thus, we hypothesize that perinatal exposure to AT1-AA infusion during pregnancy would cause F1 female offspring to develop hypertension during their first pregnancy and that AT1-AA is one mechanism of the familial connection between mothers and daughters of PE pregnancies. We infused AT1-AA (1:40) starting on gestational day (GD) 14 and allowed the dams (F0) to give birth on GD 21. Birth weight was measured within 12 hours. Offspring (F1) were aged to 3 months. One male from control litters and one female from control or AT1-AA litters were mated. Pregnancy was confirmed by vaginal smear. On GD 18 carotid catheters were inserted. On GD 19, mean arterial pressure (MAP) was measured and blood and tissues were collected. Maternal weight, pup weight, placental weight, and litter size were measured. Placental and renal preproendothelin were measured by RT-PCR. A student’s t-test was used for statistical analysis. AT1-AA female F1 offspring got pregnant earlier than normal pregnant (NP) female F1 offspring (14±2 weeks, n=14 vs 16±3 weeks, n=7, p<0.05). F1 AT1-AA pregnant offspring were smaller at gestational day 19 than F1 NP female offspring (293±5g, n=14 vs 338±7g n=7, p<0.0001). F1 AT1-AA pregnant offspring had increased MAP compared to F1 NP offspring (117±3 mmHg, n=14, p<0.05 vs 105±2 mmHg, n=7). Interestingly, there were no differences in FGR, however, F1 AT1-AA litters were significantly smaller than F1 NP litters (7±2 pups, n=14 litters vs 13±1 pups, n=7 litters, p<0.05). Placental PPET was significantly increased 9.5±2.0 fold in F1 AT1-AA dams compared to F1 NP dams. Renal PPET was also significantly increased 7.5±2.5 fold in F1 AT1-AA dams compared to F1 NP dams. These data demonstrate that perinatal AT1-AA exposure predisposes F1 female offspring to have elevated blood pressure during pregnancy supporting the hypothesis that AT1-AA may be a factor contributing to the familial risk for PE. This study was supported by NIH grants RO1HL170622 (BL), F31HD110230 (NC), and P20GM121334 (BL). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.