慢性 binge 酒精暴露致孕鼠子宫动脉功能障碍的机制。
Mechanisms Underlying Chronic Binge Alcohol Exposure-Induced Uterine Artery Dysfunction in Pregnant Rat.
机构信息
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas.
出版信息
Alcohol Clin Exp Res. 2018 Apr;42(4):682-690. doi: 10.1111/acer.13602. Epub 2018 Feb 16.
BACKGROUND
A cardinal feature of fetal alcohol syndrome is growth restriction. Maternal uterine artery adaptations to pregnancy correlate with birthweight and survival. We hypothesized that gestational binge alcohol exposure impairs maternal uterine vascular function, affecting endothelial nitric oxide (NO)-mediated vasodilation.
METHODS
Pregnant rats grouped as pair-fed control or binge alcohol exposed received a once-daily, orogastric gavage of isocaloric maltose-dextrin or alcohol, respectively. On gestational day 20, primary uterine arteries were isolated, cannulated, and connected to a pressure transducer, and functional studies were conducted by dual-chamber arteriography. Uterine arteries maintained at constant intramural pressure (90 mm Hg) were maximally constricted with thromboxane, and a dose-response for acetylcholine (Ach) was recorded.
RESULTS
The alcohol group exhibited significantly impaired endothelium-dependent, Ach-induced uterine artery relaxation (↓∼30%). Subsequently, a dose-response was recorded following inhibition of endothelium-derived hyperpolarizing factor (apamin and TRAM-34) and prostacyclin (indomethacin). Ach-induced relaxation in the pair-fed control decreased by ~46%, and interestingly, relaxation in alcohol group further decreased by an additional ~48%, demonstrating that gestational binge alcohol impairs the NO system in the primary uterine artery. An endothelium-independent sodium nitroprusside effect was not observed. Immunoblotting indicated that alcohol decreased the level of endothelial excitatory P-Ser endothelial NO synthase (eNOS) (p < 0.05) and total eNOS expression (p < 0.05) compared to both the normal and pair-fed controls. P-Ser eNOS level was also confirmed by immunofluorescence imaging.
CONCLUSIONS
This is the first study to demonstrate maternal binge alcohol consumption during pregnancy disrupts uterine artery vascular function via impairment of the eNOS vasodilatory system.
背景
胎儿酒精综合征的一个主要特征是生长受限。母体子宫动脉对妊娠的适应与出生体重和存活率相关。我们假设，妊娠期 binge 饮酒会损害母体子宫血管功能，影响内皮一氧化氮（NO）介导的血管舒张。
方法
将怀孕的大鼠分为等热量麦芽糖-糊精喂养的对照组和 binge 酒精暴露组，分别每天通过口腔灌胃给予一次。在妊娠第 20 天，分离、插管并连接压力传感器，通过双室血管造影术进行功能研究。将子宫动脉维持在恒定的壁内压（90mmHg）下，用血栓素最大收缩，记录乙酰胆碱（Ach）的剂量反应。
结果
酒精组表现出明显的内皮依赖性、Ach 诱导的子宫动脉舒张功能受损（↓∼30%）。随后，在抑制内皮衍生超极化因子（apamin 和 TRAM-34）和前列环素（吲哚美辛）后，记录了剂量反应。在对照组中，Ach 诱导的舒张减少了约 46%，有趣的是，酒精组的舒张进一步减少了约 48%，表明妊娠期 binge 饮酒会损害初级子宫动脉中的一氧化氮系统。没有观察到非内皮依赖性的硝普钠作用。免疫印迹表明，与正常对照组和对照组相比，酒精降低了内皮兴奋性 P-Ser 内皮一氧化氮合酶（eNOS）（p<0.05）和总 eNOS 表达（p<0.05）。P-Ser eNOS 水平也通过免疫荧光成像得到证实。
结论
这是第一项研究表明，妊娠期 binge 饮酒会通过损害 eNOS 血管舒张系统来破坏子宫动脉血管功能。
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