Abstract 25: Inhibition Of The Agonistic Ang II Type 1 Receptor Autoantibody In A Rat Model Of Preeclampsia Improves Uteroplacental Perfusion And Fetal Growth In Late Gestation

Abstract

Placenta ischemia, the initiating factor in preeclampsia (PE), is associated with intrauterine growth restriction (IUGR) and increased blood pressure (BP) in offspring. Yet, the only treatment for PE is delivery of the baby and placenta. The Reduced Uterine Perfusion Pressure (RUPP) rat model induced by placental ischemia at gestational day 14 (G14) mimics many facets of human PE including pregnancy-specific hypertension, an increase in the agonistic ANG II Type 1 receptor autoantibody (AT1-AA), IUGR and increased BP in the offspring. Inhibition of AT1-AA using an epitope-binding inhibitory peptide ('n7AAc') attenuates increased BP at gestational day 19 in the RUPP. Yet, whether use of ‘n7aac’ improves fetal growth and mitigates increased BP in the offspring is unknown. Thus, we tested the hypothesis that maternal administration of ‘n7aac’ improves fetal growth by attenuating reduced uterine blood flow and impaired placental remodeling. Sham or RUPP surgery was performed at G14 with administration of vehicle or ‘n7aac’ (144μg/day) via mini osmotic pump until gestational day 20 (G20). At G20 uterine artery resistance index was significantly elevated in vehicle RUPP (0.69±0.02 mm/s n=10) compared to vehicle Sham (0.48±0.02 mm/s n=8) (P<0.0001) and not increased in treated RUPP (0.49±0.02 mm/s n=10) or treated Sham (0.48±0.02 mm/s n=9). Fetal weight was significantly reduced in vehicle RUPP (3.24±0.2 g) compared to vehicle Sham (3.92±0.05 g) (P=0.013) and not decreased in treated RUPP (3.70±0.04 g) or Sham (3.98±0.10 g). Litter size of viable pups at G20 was only reduced in treated RUPP (5.3±1.4) compared to vehicle Sham (11.56±0.7) (P=0.003). Importantly, using in vivo imaging, little to no auto fluorescence of rhodamine-labeled peptide (480 μg/kg/day, n=4) was detectable in the pups at G20. Thus, our results demonstrate that maternal treatment with ‘n7aac’ in the RUPP rat model of PE improve UARI, which is associated with improved fetal weight at G20 in response to placental ischemia. Whether this benefit continues to birth and mitigates increased BP in IUGR offspring is unknown but is the focus of future studies. In conclusion, inhibition of the AT1AA during PE may not only provide benefit to the mother, but may also be associated with benefit in the offspring.