Abstract：
BACKGROUND: 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.
OBJECTIVE: This study aimed to investigate the impact of GYY4137, a slow-release H2S donor, on sFlt-1-induced hypertension in pregnant rats and examine the underlying mechanisms.
METHODS: Pregnant rats were administered sFlt-1 (6 μg/kg/day, intravenously) or vehicle from gestation day (GD) 12 to 20. A subset of these groups received GYY4137 (an H2S donor, 50 mg/kg/day, subcutaneously) from GD 16 to 20. Serum H2S levels, mean arterial blood pressure (CODA tail-cuff), uterine artery blood flow (ultrasonography), vascular reactivity to vasopressors and endothelial-dependent relaxation (myography), endothelial nitric oxide synthase (eNOS) protein expression in uterine arteries (Western blotting) were assessed. In addition, maternal weight gain, as well as fetal and placental weights, were measured.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: This study aimed to investigate the impact of GYY4137, a slow-release H2S donor, on sFlt-1-induced hypertension in pregnant rats and examine the underlying mechanisms.
METHODS: Pregnant rats were administered sFlt-1 (6 μg/kg/day, intravenously) or vehicle from gestation day (GD) 12 to 20. A subset of these groups received GYY4137 (an H2S donor, 50 mg/kg/day, subcutaneously) from GD 16 to 20. Serum H2S levels, mean arterial blood pressure (CODA tail-cuff), uterine artery blood flow (ultrasonography), vascular reactivity to vasopressors and endothelial-dependent relaxation (myography), endothelial nitric oxide synthase (eNOS) protein expression in uterine arteries (Western blotting) were assessed. In addition, maternal weight gain, as well as fetal and placental weights, were measured.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：妊娠期高血压，通常与可溶性Fms相关受体酪氨酸激酶1（sFlt-1）升高有关，对孕产妇和胎儿健康都构成重大风险。硫化氢(H2S),一个气体发射器,在高血压动物和人类中已经证明了降血压的作用。然而,其在妊娠高血压中的作用尚不清楚.
目的：本研究旨在研究缓释H2S供体GYY4137的影响，关于sFlt-1诱导的妊娠大鼠高血压，并检查其潜在机制。
方法：妊娠大鼠给药sFlt-1（6μg/kg/天，静脉内）或从妊娠日（GD）12至20日的媒介物。这些组中的一个子集接受了GYY4137(H2S供体，50毫克/千克/天，皮下）从GD16到20。血清H2S水平，平均动脉血压（CODA尾袖），子宫动脉血流（超声检查），血管对血管加压药的反应性和内皮依赖性舒张（肌电图），评估子宫动脉中内皮型一氧化氮合酶（eNOS）蛋白的表达（Westernblotting）。此外,母体体重增加,以及胎儿和胎盘的重量，被测量。
结果：sFlt-1升高降低了母体体重增加和血清H2S水平。GYY4137治疗恢复了sFlt-1大坝中的体重增加和H2S水平。sFlt-1增加了妊娠大鼠的平均动脉压，减少了子宫动脉血流。然而,用GYY4137治疗sFlt-1大坝的血压恢复正常，子宫血流恢复。sFlt-1大坝对苯肾上腺素和GYY4137表现出增强的血管收缩，可显着减轻过度的血管收缩。值得注意的是,sFlt-1受损的内皮依赖性松弛，而GYY4137通过上调eNOS蛋白水平和增强子宫动脉的血管舒张来减轻这种损害。GYY4137减轻sFlt-1诱导的胎儿生长受限。
结论：sFlt-1介导的高血压与H2S水平降低有关。用供体GYY4137补充H2S减轻高血压并改善血管功能和胎儿生长结局。这表明H2S的调节可以为管理妊娠期高血压和不良胎儿影响提供新的治疗策略。
目的：本研究旨在研究缓释H2S供体GYY4137的影响，关于sFlt-1诱导的妊娠大鼠高血压，并检查其潜在机制。
方法：妊娠大鼠给药sFlt-1（6μg/kg/天，静脉内）或从妊娠日（GD）12至20日的媒介物。这些组中的一个子集接受了GYY4137(H2S供体，50毫克/千克/天，皮下）从GD16到20。血清H2S水平，平均动脉血压（CODA尾袖），子宫动脉血流（超声检查），血管对血管加压药的反应性和内皮依赖性舒张（肌电图），评估子宫动脉中内皮型一氧化氮合酶（eNOS）蛋白的表达（Westernblotting）。此外,母体体重增加,以及胎儿和胎盘的重量，被测量。
结果：sFlt-1升高降低了母体体重增加和血清H2S水平。GYY4137治疗恢复了sFlt-1大坝中的体重增加和H2S水平。sFlt-1增加了妊娠大鼠的平均动脉压，减少了子宫动脉血流。然而,用GYY4137治疗sFlt-1大坝的血压恢复正常，子宫血流恢复。sFlt-1大坝对苯肾上腺素和GYY4137表现出增强的血管收缩，可显着减轻过度的血管收缩。值得注意的是,sFlt-1受损的内皮依赖性松弛，而GYY4137通过上调eNOS蛋白水平和增强子宫动脉的血管舒张来减轻这种损害。GYY4137减轻sFlt-1诱导的胎儿生长受限。
结论：sFlt-1介导的高血压与H2S水平降低有关。用供体GYY4137补充H2S减轻高血压并改善血管功能和胎儿生长结局。这表明H2S的调节可以为管理妊娠期高血压和不良胎儿影响提供新的治疗策略。
