Wang Xiaomin, Ali Md Ahasan, Liu Xiaoxu, Zeng Ming, Zeng Zhaoshu, Yuan Meng, Issotina Zibrila Abdoulaye, Liu Shumin, Ping Nana, Kang Yuming, Li Xuelan, Liu Jinjun
Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an, 710061, Shaanxi, China.
Shaanxi Province Blood Center, Xi'an, 710061, Shaanxi, China.
Neurochem Int. 2025 Sep;188:106004. doi: 10.1016/j.neuint.2025.106004. Epub 2025 Jun 1.
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.
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.
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.
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.
子痫前期（PE）是一种与高血压相关的妊娠并发症，其中心机制尚不清楚。胃泌素释放肽（GRP）参与中枢血压调节，然而，下丘脑室旁核（PVN）中的GRP及其受体GRPR是否参与PE的血压调节尚不清楚。
在本研究中，我们首先评估了子宫灌注压降低（RUPP）的PE大鼠模型PVN内GRP/GRPR的表达水平及其细胞分布。我们研究了用ICI-216140（1 mM/侧/天，PVN微量注射）对GRPR进行为期五天的拮抗作用对该模型PVN活性的影响。在妊娠第19天（GD19），记录平均动脉压（MAP），并采集样本进行分析。我们还研究了氯沙坦对RUPP诱导的MAP变化和PVN中GRP/GRPR表达的影响。
RUPP大鼠的MAP以及PVN中的GRP和GRPR表达增加。用ICI-216140拮抗GRPR可减弱RUPP干预引起的MAP升高以及PVN中氧化应激标志物（包括NOX2、NOX4、活性氧、NF-κB和酪氨酸羟化酶）的表达增加。虽然ICI-216140不影响1型血管紧张素II受体（AT1R）的表达，但用氯沙坦阻断AT1R可降低RUPP大鼠的MAP和GRP表达。
我们的研究结果表明，PVN中的GRP表达介导胎盘缺血诱导的高血压，并且可能依赖于AT1R活性，这为PE动物模型提供了新的药理学途径。
