Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA.
Endocrinology-Reproductive Physiology Program, University of Wisconsin, Madison, WI 53715, USA.
Int J Mol Sci. 2023 Sep 16;24(18):14180. doi: 10.3390/ijms241814180.
Perfluorooctane sulfonic acid (PFOS) exposure during pregnancy induces hypertension with decreased vasodilatory angiotensin type-2 receptor (AT2R) expression and impaired vascular reactivity and fetal weights. We hypothesized that AT2R activation restores the AT1R/AT2R balance and reverses gestational hypertension by improving vascular mechanisms. Pregnant Sprague-Dawley rats were exposed to PFOS through drinking water (50 μg/mL) from gestation day (GD) 4-20. Controls received drinking water with no detectable PFOS. Control and PFOS-exposed rats were treated with AT2R agonist Compound 21 (C21; 0.3 mg/kg/day, SC) from GD 15-20. In PFOS dams, blood pressure was higher, blood flow in the uterine artery was reduced, and C21 reversed these to control levels. C21 mitigated the heightened contraction response to Ang II and enhanced endothelium-dependent vasorelaxation in uterine arteries of PFOS dams. The observed vascular effects of C21 were correlated with reduced AT1R levels and increased AT2R and eNOS protein levels. C21 also increased plasma bradykinin production in PFOS dams and attenuated the fetoplacental growth restriction. These data suggest that C21 improves the PFOS-induced maternal vascular dysfunction and blood flow to the fetoplacental unit, providing preclinical evidence to support that AT2R activation may be an important target for preventing or treating PFOS-induced adverse maternal and fetal outcomes.
全氟辛烷磺酸（PFOS）在妊娠期间的暴露会导致高血压，表现为血管舒张性血管紧张素 II 型受体（AT2R）表达减少、血管反应性和胎儿体重受损。我们假设 AT2R 激活可以通过改善血管机制来恢复 AT1R/AT2R 平衡并逆转妊娠高血压。通过饮水（50μg/ml）使妊娠第 4-20 天的 Sprague-Dawley 大鼠暴露于 PFOS。对照组给予不含可检测到 PFOS 的饮用水。从妊娠第 15-20 天，用 AT2R 激动剂化合物 21（C21；0.3mg/kg/天，SC）对对照组和 PFOS 暴露组大鼠进行处理。在 PFOS 孕鼠中，血压升高，子宫动脉血流减少，而 C21 将这些恢复至对照水平。C21 减轻了 PFOS 孕鼠对 Ang II 的收缩反应增强，并增强了子宫动脉的内皮依赖性血管舒张。C21 的观察到的血管作用与 AT1R 水平降低、AT2R 和 eNOS 蛋白水平升高相关。C21 还增加了 PFOS 孕鼠的血浆缓激肽产生，并减轻了胎仔胎盘生长受限。这些数据表明，C21 改善了 PFOS 引起的母体血管功能障碍和胎儿胎盘单位的血流，为 AT2R 激活可能是预防或治疗 PFOS 引起的不良母婴结局的重要靶点提供了临床前证据。
