PDF(Pubmed)
Abstract：
Fetal growth restriction is a hallmark of Fetal Alcohol Syndrome (FAS) and is accompanied by maternal uterine circulatory maladaptation. FAS is the most severe form of Fetal Alcohol Spectrum Disorder (FASD), a term for the range of conditions that can develop in a fetus when their pregnant mother consumes alcohol. Alcohol exerts specific direct effects on lipids that control fundamental developmental processes. We previously demonstrated that direct in vitro application of phosphatidic acid (PA, the simplest phospholipid and a direct target of alcohol exposure) to excised uterine arteries from alcohol-exposed rats improved vascular function, but it is unknown if PA can rescue end organ phenotypes in our FASD animal model. Pregnant Sprague-Dawley rats (n = 40 total dams) were gavaged daily from gestational day (GD) 5 to GD 19 with alcohol or maltose dextrin, with and without PA supplementation, for a total of four unique groups. To translate and assess the beneficial effects of PA, we hypothesized that in vivo administration of PA concomitant with chronic binge alcohol would reverse uterine artery dysfunction and fetal growth deficits in our FASD model. Mean fetal weights and placental efficiency were significantly lower in the binge alcohol group compared with those in the control (p < 0.05). However, these differences between the alcohol and the control groups were completely abolished by auxiliary in vivo PA administration with alcohol, indicating a reversal of the classic FAS growth restriction phenotype. Acetylcholine (ACh)-induced uterine artery relaxation was significantly impaired in the uterine arteries of chronic in vivo binge alcohol-administered rats compared to the controls (p < 0.05). Supplementation of PA in vivo throughout pregnancy reversed the alcohol-induced vasodilatory deficit; no differences were detected following in vivo PA administration between the pair-fed control and PA alcohol groups. Maximal ACh-induced vasodilation was significantly lower in the alcohol group compared to all the other treatments, including control, control PA, and alcohol PA groups (p < 0.05). When analyzing excitatory vasodilatory p1177-eNOS, alcohol-induced downregulation of p1177-eNOS was completely reversed following in vivo PA supplementation. In summary, these novel data utilize a specific alcohol target pathway (PA) to demonstrate a lipid-based preventive strategy and provide critical insights important for the development of translatable interventions.
摘要：
胎儿生长受限是胎儿酒精综合症（FAS）的标志，并伴有母体子宫循环适应不良。FAS是胎儿酒精谱系障碍（FASD）最严重的形式，一个术语，指的是当怀孕的母亲饮酒时胎儿可能出现的一系列疾病。酒精对控制基本发育过程的脂质具有特定的直接作用。我们先前证明了磷脂酸(PA，最简单的磷脂和酒精暴露的直接目标）从酒精暴露的大鼠切除的子宫动脉改善了血管功能，但在我们的FASD动物模型中，PA能否挽救终末器官表型尚不清楚。从妊娠日（GD）5到GD19，每天用酒精或麦芽糖糊精对怀孕的Sprague-Dawley大鼠（n=40个总水坝）进行灌胃，有和没有PA补充，总共有四个独特的群体。为了翻译和评估PA的有益效果，在我们的FASD模型中,我们假设体内给予PA与慢性酗酒会逆转子宫动脉功能障碍和胎儿生长缺陷.与对照组相比，酗酒组的平均胎儿体重和胎盘效率显着降低（p<0.05）。然而,酒精和对照组之间的这些差异被酒精辅助体内PA给药完全消除，表明经典FAS生长限制表型的逆转。与对照组相比，乙酰胆碱（ACh）诱导的子宫动脉松弛在慢性体内酗酒大鼠的子宫动脉中明显受损（p<0.05）。在整个怀孕期间体内补充PA可以逆转酒精引起的血管舒张缺陷；在配对喂养的对照组和PA酒精组之间，体内PA给药后未检测到差异。与所有其他治疗方法相比，酒精组的最大ACh诱导的血管舒张功能显着降低，包括控制，控制PA,和酒精PA组(p<0.05)。在分析兴奋性血管舒张p1177-eNOS时，体内补充PA后，酒精诱导的p1177-eNOS下调被完全逆转。总之,这些新数据利用特定的酒精靶途径(PA)来证明基于脂质的预防策略,并为开发可翻译干预措施提供重要的关键见解.
