Fetal cerebrovascular eCB system as a target of maternal alcohol consumption

胎儿脑血管eCB系统作为母体饮酒的目标

• 批准号: 8570401
• 负责人: Anna Bukiya
• 金额: $ 17.81万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-05 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8570401
• 关键词: 2-arachidonylglycerol; Address; Adult; Adverse effects; Affect; Agonist; Alcohol consumption; Alcohols; Animal Model; Area; Arteries; Attention; Attenuated; Behavioral; Birth; Blood Circulation; Blood Vessels; Blood flow; Brain; Brain Injuries; CNR1 gene; Calcium; Calcium Channel Blockers; Caliber; Cardiovascular Diseases; Cerebrovascular Circulation; Cerebrum; Child; Cognitive; Congenital Abnormality; Data; Defect; Development; Developmental Disabilities; Elements; Endocannabinoids; Endothelium; Ensure; Enzymes; Etiology; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetus; Functional disorder; Goals; Immunohistochemistry; Incidence; Individual; Live Birth; Magnetic Resonance Imaging; Mass Fragmentography; Measurement; Measures; Mediating; Memory impairment; Mind; Modeling; Monoacylglycerol Lipases; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neurons; Nutrient; Oxygen; Papio; Pathology; Pharmacologic Substance; Pharmacology; Physiology; Plastics; Potassium; Pregnancy; Prevention; Primates; Public Health; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; School-Age Population; Second Pregnancy Trimester; Serum; Sheep; Signal Transduction; Smooth Muscle; Stimulus; Symptoms; System; Task Performances; Testing; Third Pregnancy Trimester; Time; Tissues; Vascular Endothelium; Vascular Smooth Muscle; Vasodilator Agents; Work; alcohol consumption during pregnancy; alcohol exposure; anandamide; base; binge drinking; brain size; cerebral artery; cerebrovascular; channel blockers; density; disability; drinking; fatty acid amide hydrolase; fetal; fetal blood; flexibility; in utero; middle cerebral artery; migration; nervous system disorder; obesity treatment; pregnant; processing speed; public health relevance; receptor; receptor function; response; stable isotope; treatment strategy; voltage

DESCRIPTION (provided by applicant): The incidence of fetal alcohol spectrum disorders (FASD) ranges from 20 to 50 per 1,000 live births in a worldwide studies of school-age children and is estimated to affect at least 1% of all births in the US (www.cdc.gov). The etiology of FASD is poorly understood, and is usually considered to have neuronal origin. Indeed, maternal alcohol consumption results in diminished neuronal migration, oligodenrocytes and microglial development. However, little attention is given to fetal cerebral circulation as a target of maternal drinking. Fetal cerebral blood flow is critical for oxygen and nutrient delivery to developing brain and vascular responses of cerebral arteries are fundamental in the fetal adaptation to the adverse intrauterine conditions. The experimental work in animal models showed vasodilating effect of maternal alcohol consumption in fetal cerebral arteries. The mechanism(s) of this effect remains unknown. Endocannabinoids (eCBs: anandamide, 2-arachydonoylglycerol) are powerful vasodilators in adult circulation, and our preliminary data show expression of eCB receptor CB1 in fetal blood vessels. Therefore, we hypothesize that maternal alcohol consumption during second half of gestation alters fetal cerebral artery contractility via eCB dependent mechanism(s). Using a primate model (baboon, Papio spp.) of pregnancy and combining Doppler examination of fetal cerebral blood flow, stable isotope dilution gas chromatography/mass spectrometry, immunohistochemistry, RT-PCR, pressurized cerebral artery diameter measurements and selective pharmacology, we will: 1) Establish whether maternal binge drinking during the second half of gestation alters key elements of the endocannabinoid system in fetal cerebral arteries: circulating level of anandamide and 2- arachydonoylglycerol, tissue expression of their metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively, and tissue expression of CB1 receptor for eCBs; 2) Determine whether maternal binge drinking alters eCB-mediated control of vascular contractility and unveil underlying subcellular mechanism(s) by testing eCB-induced pressurized fetal cerebral artery diameter change in the presence of CB1 receptor antagonist, calcium/voltage-gated potassium (BK) and voltage-gated Ca2+ channel blockers. Our study will establish for the first time role of fetal cerebral artery eCB system in the respons of fetal circulation to maternal alcohol consumption. Successful completion of the proposed studies will open conceptually new venue for the prevention and treatment of FASD. Current work will be also highly relevant in the lieu of rapidly growing area of eCB manipulation for treatment of obesity, cardiovascular and neurological disorders, as pharmaceutical alteration of vascular eCB system may cause adverse effects on fetal brain development.

描述（由申请人提供）：根据一项针对学龄儿童的全球研究，胎儿酒精谱系障碍 (FASD) 的发病率范围为每 1,000 名活产 20 至 50 名，估计影响美国所有新生儿的至少 1% （www.cdc.gov）。 FASD 的病因尚不清楚，通常被认为具有神经元起源。事实上，母亲饮酒会导致神经元迁移、少突胶质细胞和小胶质细胞发育减少。然而，很少有人关注胎儿脑循环作为母亲饮酒的目标。胎儿脑血流对于向发育中的大脑输送氧气和营养物质至关重要，脑动脉的血管反应是胎儿适应不利的宫内条件的基础。动物模型的实验工作表明，母体饮酒对胎儿脑动脉有血管舒张作用。这种效应的机制仍然未知。内源性大麻素（eCB：anandamide、2-arachydonoylglycerol）是成人循环中强大的血管扩张剂，我们的初步数据显示胎儿血管中 eCB 受体 CB1 的表达。因此，我们假设妊娠后半期母亲饮酒会通过 eCB 依赖性机制改变胎儿脑动脉收缩力。使用怀孕的灵长类动物模型（狒狒、狒狒属）并结合胎儿脑血流的多普勒检查、稳定同位素稀释气相色谱/质谱、免疫组织化学、RT-PCR、加压脑动脉直径测量和选择性药理学，我们将： 1) 确定母亲在妊娠后半期的暴饮暴食是否会改变胎儿脑动脉内源性大麻素系统的关键要素：anandamide 和 2- 的循环水平花生四烯酰甘油，其代谢酶脂肪酸酰胺水解酶 (FAAH) 和单酰甘油脂肪酶 (MAGL) 的组织表达，以及 eCB 的 CB1 受体的组织表达； 2) 通过在存在 CB1 受体拮抗剂、钙/电压门控钾 (BK) 的情况下测试 eCB 诱导的加压胎儿大脑动脉直径变化，确定母亲酗酒是否会改变 eCB 介导的血管收缩性控制，并揭示潜在的亚细胞机制）和电压门控 Ca2+ 通道阻滞剂。我们的研究将首次确定胎儿大脑动脉 eCB 系统在胎儿循环对母体饮酒反应中的作用。拟议研究的成功完成将为预防和治疗 FASD 开辟新的概念领域。目前的工作也将与快速增长的 eCB 治疗肥胖、心血管和神经系统疾病领域密切相关，因为血管 eCB 系统的药物改变可能会对胎儿大脑发育造成不利影响。