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）：在全球对学龄儿童的研究中，胎儿​​酒精谱系障碍（FASD）的发生率在每1000名活生生中20至50次，估计会影响美国所有分娩的至少1％（www.cdc.gov）。 FASD的病因知之甚少，通常被认为具有神经元来源。实际上，孕产妇的饮酒会导致神经元迁移，少突上细胞和小胶质细胞发育减少。但是，很少关注胎儿脑循环作为母亲饮酒的目标。胎儿的脑血流量对于氧气至关重要，并且养分向发育中的大脑递送，而大脑动脉的血管反应对于胎儿适应不良内宫内条件至关重要。动物模型中的实验工作表明，胎儿饮酒对胎儿脑动脉的血管舒张作用。这种作用的机制仍然未知。内源性大麻素（ECB：Anandamide，2-芳基烯丙基甘油）是成人循环中强大的血管扩张剂，我们的初步数据显示欧洲央行受体CB1在胎儿血管中的表达。因此，我们假设妊娠后半部分的孕产妇饮酒会通过欧洲央行依赖机制改变胎儿脑动脉收缩性。使用妊娠妊娠的灵长类动物模型（狒狒，帕皮奥属），并结合胎儿大脑血流的多普勒检查，稳定的同位素稀释气体色谱/质谱仪，免疫组织化学，RT-PCR，加压式脑动脉直径测量和选择性元素在元素中，我们是否会饮用gest gest gester：1）胎儿脑动脉中的内源性大麻素系统：anandamide和2- 2-芳基二烯丙基甘油的循环水平，其代谢酶的组织表达脂肪酸酰胺水解酶（FAAH）和单酰基甘油甘油脂肪酶（MAGL），以及CB1受体的组织表达2）确定产妇的暴饮暴食是否通过测试CB1受体拮抗剂，钙/电压盖孔（BK）和Voltage-gromtage-Glocker blocker的CB1受体拮抗剂而在存在CB1受体拮抗剂的存在下，通过测试ECB诱导的胎儿脑脑动脉直径的变化来改变对欧洲欧洲央行介导的血管收缩性和潜在亚细胞机制的控制。我们的研究将确定胎儿脑动脉系统在胎儿循环对孕产妇饮酒的反应中的首次角色。成功完成拟议的研究将在概念上为预防和治疗FASD开放新的场所。由于血管欧洲央行系统的药物改变可能会对胎儿脑发育造成不利影响，因此目前的工作也将在欧洲央行操纵方面快速增长的领域高度相关。