Alcohol & Maternal Uterine Vascular Adaptations in Pregnancy Maternal alcohol abuse during pregnancy can result in Fetal Alcohol Spectrum Disorders (FASD), a lifelong disability characterized by a range of growth and developmental deficits. Current estimates of FASD prevalence is about 2-5% among young school children in the United States. Efforts to successfully prevent or ameliorate the teratogenic effects of ethanol have been impeded, at least in part, by a limited understanding of alcohol's complex mechanisms of action involving multiple organ systems. A normal pregnancy is associated with major uterine circulatory adaptations that directly relates to fetal growth, neonatal birth weights and survival. A cardinal feature of fetal alcohol syndrome is growth restriction, but traditionally alcohol studies have focused on brain/behavioral deficits, and little attention has been paid to critical gestational uterine vascular adaptations. We herein show novel preliminary data that alcohol impairs the exquisite regulation of gestational uterine circulatory adaptations in rat bing alcohol model. We herein hypothesize that chronic binge alcohol exposure during pregnancy impairs maternal uterine artery vascular adaptations via endothelial nitric oxide (NO) system dysregulation.
Aim#1 will test the hypothesis that binge alcohol exposure in pregnancy leads to impaired endothelium-dependent maternal uterine artery relaxation. Following binge paradigm, we will assess growth indices, and utilize wire myography to study agonist-induced uterine artery relaxation in endothelium-intact/denuded vessels from saline control, pair-fed nutrition control, and alcohol rats.
Aim#2 will test if binge alcohol impairs uterine artery relaxation via endothelium-derived NO relative to prostacyclin/endothelium-derived hyperpolarizing factor, decreases uterine artery NO production, endothelial NO synthase (eNOS) expression, and impairs eNOS multi-site phosphorylation.
Aim#3 will test if binge alcohol decreases uterine artery NO, decreases excitatory Pser1177eNOS levels, and increases inhibitory Pthr495eNOS levels via ERK/AMPK pathway, and alcohol effects on endothelial [Ca+2]i transients.
In Aims#2 and #3, we will assess uterine artery relaxation after blocking major vasodilatory pathways and conduct mechanistic studies with/without eNOS activity/multi-site phosphorylation-regulating pathway antagonists via RT-PCR, immunoblotting, histology, fluorescent imaging and spectrophotometry. Simultaneous [Ca2+]i-NO fluorescent imaging will be performed utilizing high-speed excitation/emission wavelength switching system. Our proposal explores a new frontier of gestational alcohol research by developing the first mechanistic framework for binge alcohol-induced uterine artery adaptations and identifying alcohol targets in an in vivo model. In alignment with NIAAA FY14 Strategic Plan, our proposal utilizes powerful methods and presents a new maternal-inclusive paradigm to the FAS field and predicts that a more effective intervention will require innovative pharmacologic targeting of maternal systems, especially the critical uterine circulation, in order to predict and propose a therapy that will have a real promie as a preventive strategy.
Maternal alcohol exposure can result in fetal alcohol spectrum disorders, a lifelong disability characterized by a span of growth and developmental deficits affecting 2-5% of young school children in the United States. Efforts to successfully prevent or ameliorate the deleterious effects of maternal alcohol consumption have been impeded in part by a limited understanding of alcohol's complex mechanisms of action involving multiple organ systems. The proposed R01 studies will explore a new frontier of gestational alcohol research by exploring critical maternal uterine circulatory adaptations, developing the first reproductive vascular mechanistic framework for alcohol actions, and identifying specific alcohol targets utilizing state of the art functional studies in an in vivo binge drinking model.
| Naik, Vishal D; Davis-Anderson, Katie; Subramanian, Kaviarasan et al. (2018) Mechanisms Underlying Chronic Binge Alcohol Exposure-Induced Uterine Artery Dysfunction in Pregnant Rat. Alcohol Clin Exp Res 42:682-690 |
| Lunde-Young, Raine; Davis-Anderson, Katie; Naik, Vishal et al. (2018) Regional dysregulation of taurine and related amino acids in the fetal rat brain following gestational alcohol exposure. Alcohol 66:27-33 |
| Davis-Anderson, Katie L; Wesseling, Hendrik; Siebert, Lara M et al. (2018) Fetal regional brain protein signature in FASD rat model. Reprod Toxicol 76:84-92 |
| Davis-Anderson, Katie L; Berger, Sebastian; Lunde-Young, Emilie R et al. (2017) Placental Proteomics Reveal Insights into Fetal Alcohol Spectrum Disorders. Alcohol Clin Exp Res 41:1551-1558 |
| Naik, Vishal D; Lunde-Young, Emilie R; Davis-Anderson, Katie L et al. (2016) Chronic binge alcohol consumption during pregnancy alters rat maternal uterine artery pressure response. Alcohol 56:59-64 |
| Lunde, Emilie R; Washburn, Shannon E; Golding, Michael C et al. (2016) Alcohol-Induced Developmental Origins of Adult-Onset Diseases. Alcohol Clin Exp Res 40:1403-14 |
| Ampey, Bryan C; Morschauser, Timothy J; Ramadoss, Jayanth et al. (2016) Domain-Specific Partitioning of Uterine Artery Endothelial Connexin43 and Caveolin-1. Hypertension 68:982-8 |
