Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA.
Department of Obstetrics and Gynecology, University of California, Irvine, CA, USA.
Biol Reprod. 2024 Oct 14;111(4):879-889. doi: 10.1093/biolre/ioae103.
Gestational hypertension, often associated with elevated soluble Fms-related receptor tyrosine kinase 1 (sFlt-1), poses significant risks to both maternal and fetal health. Hydrogen sulfide (H2S), a gasotransmitter, has demonstrated blood pressure-lowering effects in hypertensive animals and humans. However, its role in pregnancy-induced hypertension remains unclear. This study investigated the impact of GYY4137, a slow-release H2S donor, on sFlt-1-induced hypertension in pregnant rats . Pregnant rats were administered sFlt-1 (6 μg/kg/day, intravenously) or vehicle from gestation day (GD) 12-20. A subset of these groups received GYY4137 ( 50 mg/kg/day, intraperitoneal) from GD 16-20. Serum H2S levels, mean arterial blood pressure, uterine artery blood flow, and vascular reactivity were assessed. Elevated sFlt-1 reduced both maternal weight gain and serum H2S levels. GYY4137 treatment restored both weight gain and H2S levels in sFlt-1 dams. sFlt-1 increased mean arterial pressure and decreased uterine artery blood flow in pregnant rats. However, treatment with GYY4137 normalized blood pressure and restored uterine blood flow in sFlt-1 dams. sFlt-1 dams exhibited heightened vasoconstriction to phenylephrine and GYY4137 significantly mitigated the exaggerated vascular contraction. Notably, sFlt-1 impaired endothelium-dependent relaxation, while GYY4137 attenuated this impairment by upregulating eNOS protein levels and enhancing vasorelaxation in uterine arteries. GYY4137 mitigated sFlt-1-induced fetal growth restriction. In conclusion, sFlt-1 mediated hypertension is associated with decreased H2S levels. Replenishing H2S with the donor GYY4137 mitigates hypertension and improves vascular function and fetal growth outcomes. This suggests modulation of H2S could offer a novel therapeutic strategy for managing gestational hypertension and adverse fetal effects.
妊娠期高血压，常与可溶性 Fms 相关酪氨酸激酶 1（sFlt-1）升高相关，对母婴健康均构成重大风险。硫化氢（H2S）作为一种气体递质，在高血压动物和人类中已显示出降压作用。然而，其在妊娠相关性高血压中的作用尚不清楚。本研究旨在探讨慢释放 H2S 供体 GYY4137 对妊娠大鼠 sFlt-1 诱导的高血压的影响。妊娠大鼠于妊娠第 12-20 天（GD）给予 sFlt-1（6μg/kg/天，静脉内）或载体。这些组中的一部分从 GD 16-20 天给予 GYY4137（50mg/kg/天，腹腔内）。评估血清 H2S 水平、平均动脉血压、子宫动脉血流和血管反应性。升高的 sFlt-1 降低了母体体重增加和血清 H2S 水平。GYY4137 治疗可恢复 sFlt-1 母鼠的体重增加和 H2S 水平。sFlt-1 增加了妊娠大鼠的平均动脉压并减少了子宫动脉血流。然而，GYY4137 治疗可使 sFlt-1 母鼠的血压正常化并恢复子宫血流。sFlt-1 母鼠对苯肾上腺素的血管收缩反应增强，而 GYY4137 显著减轻了血管的过度收缩。值得注意的是，sFlt-1 损害了内皮依赖性松弛，而 GYY4137 通过上调 eNOS 蛋白水平和增强子宫动脉的血管松弛来减轻这种损害。GYY4137 减轻了 sFlt-1 引起的胎儿生长受限。总之，sFlt-1 介导的高血压与 H2S 水平降低有关。用供体 GYY4137 补充 H2S 可减轻高血压并改善血管功能和胎儿生长结局。这表明调节 H2S 可能为治疗妊娠期高血压和不良胎儿影响提供一种新的治疗策略。
