Pyridostigmine attenuates placental-ischemia-upregulated placental angiotensin II type 1 receptor in rats

Preeclampsia (PE) is associated with increased activation and sensitivity of the Angiotensin II type 1 receptor (AT1R) and inflammation. In this work, we assessed the effect of Pyridostigmine (PYR), with reported anti-inflammatory properties, on placental AT1R in a rat model of PE with placental ischemia. AT1R expression in the placenta from pregnant women (with and without PE) was assessed. Pregnant rats underwent sham or reduced uterine perfusion pressure (RUPP) operation on gestational day 14 (GD14). Dams were treated with either losartan (20 mg/kg/day) or PYR (20 mg/kg/day) or water for five days. Blood pressure and feto-maternal data were collected and placental samples were harvested and processed for molecular analysis. The human trophoblast (HTR-8/SVneo) cell lines were stimulated with Angiotensin II to activate AT1R and treated with Acetylcholine (ACh) to simulate the effects of PYR-increased ACh on trophoblasts. RUPP upregulated the placental AT1R expression. We confirmed that losartan lowers the mean arterial pressure (MAP) in RUPP rats and showed that losartan inhibited RUPP-upregulated placental AT1R, NOX4, TNF-α, IL-1β, and NF-κBp65. On the other hand, PYR lowered the elevated MAP in RUPP and inhibited the placental expression of AT1R, NOX4, TNF-α, IL-1β and NF-κBp65 and reduced the circulating and placental AChE activities. At the cellular level, ACh reduced the angiotensin II-increased NOX4 and NF-κBp65 expressions in the HTR-8/SVneo cell line. This study has confirmed the anti-hypertensive effects of losartan and that of PYR and revealed the anti-inflammatory effect of AT1R antagonism with losartan and the ability of PYR to mitigate the expression and the signaling of placental AT1R.