成年子代暴露于产前缺氧中增强的血栓素 A 介导的血管收缩的机制存在性别特异性差异。

Sex-specific differences in the mechanisms for enhanced thromboxane A-mediated vasoconstriction in adult offspring exposed to prenatal hypoxia.

机构信息

Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, T6G 2R3, Canada.

Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, T6G 2R3, Canada.

出版信息

Biol Sex Differ. 2024 Jun 19;15(1):52. doi: 10.1186/s13293-024-00627-x.

DOI:10.1186/s13293-024-00627-x

PMID:38898532

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11188502/

Abstract

BACKGROUND

Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A (TxA) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment.

METHODS

Pregnant Sprague-Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O) or hypoxia (11% O) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence.

RESULTS

Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels.

CONCLUSIONS

Prenatal hypoxia increased TxA vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring.

摘要

背景

产前缺氧是一种常见的妊娠并发症，可导致成年后代心血管功能受损。它导致成年后代的冠状动脉和肠系膜动脉舒张功能受损，这是由于一氧化氮（NO）减少所致。血栓素 A（TxA）是心血管疾病中增加的一种强有力的血管收缩剂，但它在产前缺氧影响中的作用尚不清楚。为了预防产前缺氧引起的心血管疾病风险，我们已经测试了一种使用纳米颗粒包裹的线粒体抗氧化剂（nMitoQ）的母体治疗方法。我们假设产前缺氧通过降低 NO 调节增强成年后代的血管 TxA 反应，而母体 nMitoQ 治疗可能会预防这种情况。

方法

妊娠 Sprague-Dawley 大鼠在妊娠第 15 天（GD15）接受单次静脉注射（100 μL）载体（生理盐水）或 nMitoQ（125 μmol/L），并从 GD15 至 GD21 暴露于常氧（21% O）或缺氧（11% O）（足月= 22 天）。从 4 个月大的雌性和雄性后代中分离出冠状动脉和肠系膜动脉，并使用线描记术评估 U46619（TxA 类似物）引起的血管收缩反应。在肠系膜动脉中，使用 L-NAME（泛 NOS（NOS）抑制剂）评估 NO 调节。通过免疫荧光评估肠系膜动脉内皮（e）NOS 和 TxA 受体表达、超氧化物和 3-硝基酪氨酸水平。

结果

产前缺氧导致雌性后代的冠状动脉和肠系膜动脉对 U46619 的反应性增加，而雄性后代的反应性增加程度较小，nMitoQ 可预防这种情况。在雌性中，产前缺氧生理盐水处理的雌性肠系膜动脉中 L-NAME 的影响降低，3-硝基酪氨酸水平降低。在雄性中，L-NAME 增加了肠系膜动脉中 U46619 的反应，但产前缺氧增加了 TxA 受体的表达。eNOS 或超氧化物水平没有变化。