Blockade of gastrin-releasing peptide receptor in the PVN alleviates maternal vascular and placental dysfunction in preeclamptic rat.

Preeclampsia (PE) is characterized by placental ischemia-induced systemic inflammation, oxidative stress, and maternal vascular dysfunction. We previously reported that upregulated gastrin-releasing peptide (GRP) and its receptor (GRPR) within the hypothalamic paraventricular nucleus (PVN) of PE rats contribute to the progression of PE. However, whether such central upregulation contributes to the peripheral organs damage in PE remains unknown. This study investigated the protective effects of the GRPR antagonist ICI-216140, administered via PVN microinjection, on mesenteric arteries and placenta in the reduced uterine perfusion pressure (RUPP) rat model initiated on gestational day (GD) 14. GRPR was antagonized with ICI-216140 (1 mM/side/day, PVN microinjection) from GD14 to GD19. On GD19, the mean arterial pressure (MAP) was recorded via carotid artery catheterization, the urinary albumin-to-creatinine ratio (ACR) and plasmatic norepinephrine were determined. Mesenteric arteries function and structure were characterized via isometric myography and H&E staining, while mitochondrial dynamics and biogenesis were evaluated through immunofluorescence and Western blotting. Additionally, inflammatory and oxidative stress markers in placentae and mesenteric arteries were assessed. Microinjection of ICI-216140 in the PVN prevented RUPP-increased MAP, proteinuria and circulating norepinephrine. In addition to suppressing inflammation and oxidative stress in both placentae and mesenteric arteries, ICI-216140 alleviated structural remodeling and contractile dysfunction, and ameliorated the imbalance in mitochondrial dynamics and biogenesis within mesenteric arteries. Our findings suggest that central antagonism of GRPR in the PVN reduced the hallmark features of PE, including hypertension, proteinuria, vascular dysfunction, and placental damage, underscoring the therapeutic potential of central interventions in preventing multi-organ damage.