Abstract Body:
Preeclampsia (PE) is new-onset hypertension and multi-organ dysfunction following the 20^th week of gestation. Female PE children are at elevated risk for PE during pregnancy, indicating a familial connection. 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 postpartum maternal circulation. We have previously shown that perinatal exposure to AT1-AA causes adult female first generation (F1) offspring (OS) to have elevated blood pressure. However, the role of perinatal AT1-AA exposure to increase the risk for hypertension and immune activation during pregnancy is unknown. Thus, we hypothesize that perinatal exposure to AT1-AA would cause F1 AT1-AA female OS to develop a PE phenotype during pregnancy.

We infused AT1-AA (1:40) starting on gestational day (GD)14 and allowed the dams (F0) to give birth. Birth weight was measured within 12 hours. OS were aged to 3 months. Control males and control or AT1-AA females were mated. Pregnancy was confirmed by vaginal smear. On GD18 carotid catheters were inserted. On GD19, mean arterial pressure (MAP) was measured and blood and tissues were collected. Weights and litter size were measured. Placental and renal preproendothelin were measured by RT-PCR. Immune cells were measured with flow cytometry. A student’s t-test was used for statistical analysis.

F1 AT1-AA pregnant OS had increased MAP and smaller litters compared to F1 NP OS (117±3 mmHg, p<0.05 vs 105±2 mmHg) (7±2 pups, vs 13±1 pups, p<0.05). Placental T helper cells were significantly increased in F1 AT1-AA OS (34±3 % gated) compared to F1 NP OS (16±3 % gated) with decreased T regulatory cells in F1 AT1-AA OS (0.44±0.12 % gated) compared to F1 NP OS (1.27±0.40 % gated). AT1-AA female F1 OS got pregnant earlier than normal pregnant (NP) female F1 OS (14±2 weeks, vs 16±3 weeks, p<0.05). F1 AT1-AA pregnant OS were smaller at gestational day 19 than F1 NP OS (293±5g, vs 338±7g, p<0.0001). Placental PPET and renal PPET were significantly increased 9.5±2.0 fold; 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 OS to have elevated blood pressure and inflammation during pregnancy supporting the hypothesis that AT1-AA may be a factor contributing to the familial risk for PE.