Gastrin-releasing peptide in the paraventricular nucleus exerts hypertensive effects in preeclampsia

Background: Preeclampsia (PE) is a pregnancy complication associated with hypertension, whose central mechanism remains unclear. Gastrin-releasing peptide (GRP) is involved in the regulation of central blood pressure, however, whether GRP and its receptor, GRPR, in the paraventricular nucleus of the hypothalamus (PVN) are involved in blood pressure regulation in PE is unknown. Methods: In this study, we initially assessed GRP/GRPR expression levels and their cellular distribution within the PVN of a PE rat model with reduced uterine perfusion pressure (RUPP). We investigated the effect of five-day antagonism of GRPR with ICI-216140 (1 mM/side/day, PVN microinjection) on PVN activity in this model. On gestational day 19 (GD19), the mean arterial pressure (MAP) was recorded, and samples were collected for analysis. We also investigated the effect of losartan on RUPP-induced changes in MAP and GRP/GRPR expression in the PVN. Results: RUPP rats exhibited increased MAP, and GRP and GRPR expression in the PVN. GRPR antagonism with ICI-216140 attenuated RUPP intervention-increased MAP and expression of oxidative stress markers including NOX2, NOX4, and reactive oxygen species, NF-κB, and tyrosine hydroxylase in the PVN. While ICI-216140 did not affect the expression of angiotensin II receptor type 1 (AT1R), the blockade of AT1R with losartan decreased MAP 2and GRP expression in RUPP rats. Conclusions: Our findings suggest that GRP expression in the PVN mediates placental ischemia-induced hypertension and may depend on AT1R activity, which provides new pharmacological avenues for animal models of PE.