ELECTRONIC CIGARETTE VAPING & VASCULAR SEQUELAE IN THE UTERUS DURING PREGNANCY.

电子烟

• 批准号: 10459954
• 负责人: Jayanth Ramadoss
• 金额: $ 22.3万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-05 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459954
• 关键词: Address; Animals; Arteries; Arteriographies; Atomizer; Birth Weight; Blood Pressure; Blood Vessels; Blood flow; Cardiac Output; Cardiovascular Diseases; Cardiovascular system; Catheterization; Chemicals; Consensus; Custom; Data; Devices; Dose; Educational workshop; Electrocardiogram; Electronic cigarette; Endothelium; Engineering; Enzymes; Epoprostenol; Fetal Growth; Fetal Growth Retardation; Fetus; Fostering; Frequencies; Gases; General Population; Glycerol; Growth; Health; High Pressure Liquid Chromatography; Histologic; Human; Immunoblotting; Impairment; Inhalation; Knowledge; Liquid substance; Mediating; Mediator of activation protein; Messenger RNA; Methods; Microspheres; Modeling; Molecular; Molecular Genetics; Mothers; NOS3 gene; National Heart, Lung, and Blood Institute; Neonatal; Nicotine; Nitric Oxide; Nutrient; Operative Surgical Procedures; Outcome; Oxygen; Pathway interactions; Pharmacology; Phenocopy; Phenotype; Policies; Positioning Attribute; Pregnancy; Pregnancy Complications; Pregnant Women; Production; Propylene Glycols; Public Health; RNA Interference; Rattus; Recommendation; Relaxation; Research; Research Design; Risk; Signal Transduction; Smoking; Surgeon; System; Technology; Testing; Time; Tobacco use; Transcript; Transgenes; Ultrasonography; United States National Institutes of Health; Uterus; Vascular Diseases; Vasodilator Agents; Woman; base; combustible cigarette; commercialization; e-cigarette aerosols; electronic cigarette use; exposed human population; frontier; genetic manipulation; hemodynamics; indexing; pregnant; pressure; protein expression; public education; reproductive; response; tobacco user; tool; transcriptome; vaping; vapor; vascular injury

ELECTRONIC CIGARETTE VAPING & VASCULAR SEQUELAE IN THE UTERUS DURING PREGNANCY Despite serious pregnancy complications, 50% of women who use tobacco products will continue to do so during pregnancy. A recent 2017 study estimates as many women use electronic-cigarettes (e-cigs) as conventional cigarettes during pregnancy. One major reason for this alarming data is that traditional tobacco users view vaping during pregnancy as a “safer” alternative. However, e-cig vapor reveals a myriad of chemicals which may be harmful to both the mother and the fetus. Using our well-established pregnant rat model, we obtained preliminary data utilizing a state-of-the-art custom-engineered e-cig atomizer that offered a translational inhalation delivery method and generated vapor profiles directly comparable to human vaping. The preliminary data demonstrated e-cig-induced major fetal growth deficit and provides the first evidence for impaired gestational circulatory adaptations including uterine blood flow, the prime regulator of gas and nutrient delivery from mother to fetus. Aim#1 will test if vaping e-cig base (propylene glycol: glycerin (80:20)) alone or with increasing doses of nicotine produce a dose-dependent effect on uterine blood flow (UBF) and fetal growth response. Further, we will test if there are e-cig-induced systemic cardiovascular adaptations during pregnancy. We will assess reproductive vascular and systemic cardiovascular adaptations of e-cig base alone or with increasing doses of nicotine utilizing high frequency ultrasonography, TTE, ECG, Luminex xMAP technology, surgical catheterization for blood pressure, and microsphere-based flow assessment. Aim#2 will test if vaping e-cig will impair uterine artery relaxation via the endothelium-derived NO vs. EDHF vs. PGI2 pathways (the three vasodilators that entirely regulate primary uterine artery blood flow in pregnancy). We will pharmacologically block combinations of endothelial-derived vasodilator pathways using pressure arteriography, and dissect impaired cell signaling utilizing HPLC, histological approaches, immunoblotting, and other molecular tools. Aim#3 will test if re-capitulating e-cig- induced decreased UBF in the absence of e-cig produces fetal growth restriction, and if restoring e-cig- impaired-UBF rescues the growth restriction phenotypes of the e-cig-treated animals. We will phenocopy using RNA interference-mediated suppression of mRNA transcripts of endothelium-dependent vasodilatory mediators, and re-create e-cig induced decreases in UBF in the absence of e-cig vaping. Using lentiviral expressing transgene(s) to restore UBF, we will determine if this can rescue the growth restriction phenotypes of e-cig-treated animals. Our proposal explores a new frontier of gestational research developing the first mechanistic framework for e-cig vaping-induced uterine circulatory adaptations in a model that offers a translational inhalation delivery and vapor profiles comparable to human vaping. The proposed studies on the health effects of e-cigs during pregnancy will facilitate applicable policy implementation on potential risks these devices pose to the public.

电子烟蒸汽和血管后遗症在子宫在怀孕期间 尽管有严重的妊娠并发症，50%的使用烟草产品的妇女将继续这样做， 所以在怀孕期间。2017年的一项研究估计，使用电子烟的女性人数与使用电子烟的女性人数一样多， 在怀孕期间吸烟。这一令人震惊的数据的一个主要原因是，传统烟草 用户认为怀孕期间使用电子烟是一种“更安全”的选择。然而，电子烟蒸汽揭示了无数的 可能对母亲和胎儿都有害的化学物质。 使用我们完善的妊娠大鼠模型，我们利用最先进的 定制设计的电子烟雾化器，其提供平移吸入递送方法并产生蒸汽 与人类吸电子烟的情况直接相当。初步数据表明，电子烟诱导的主要胎儿 生长缺陷，并提供了第一个证据，损害妊娠循环适应，包括子宫 血液流动，从母亲到胎儿的气体和营养输送的主要调节器。目标#1将测试是否vaping电子烟 单独使用或与递增剂量的尼古丁一起使用时， 对子宫血流（UBF）和胎儿生长反应的影响。此外，我们将测试是否有电子烟引起的 怀孕期间的全身性心血管适应。我们将评估生殖血管和全身 电子烟碱单独或与增加剂量的尼古丁一起使用高频的心血管适应性 超声检查、TTE、ECG、Luminex xMAP技术、血压外科导管插入术，以及 基于微球的流动评估。目标#2将测试电子烟是否会通过子宫动脉舒张损害子宫动脉舒张。 内皮源性NO vs. EDHF vs. PGI 2途径（完全调节原发性高血压的三种血管舒张剂） 妊娠期子宫动脉血流）。我们将阻断内皮衍生的 使用压力动脉造影术的血管扩张剂途径，并使用HPLC剖析受损的细胞信号传导， 组织学方法、免疫印迹和其他分子工具。目标#3将测试是否重新投降电子烟- 在没有电子烟的情况下，诱导的UBF减少会导致胎儿生长受限，如果恢复电子烟， 受损的UBF挽救了电子烟处理的动物的生长限制表型。我们将使用 RNA干扰介导的内皮依赖性血管舒张因子mRNA转录抑制 介质，并在没有电子烟的情况下重新创建电子烟诱导的UBF减少。使用慢病毒 表达转基因以恢复UBF，我们将确定这是否可以挽救生长限制表型 使用电子烟的动物 我们的建议探索了一个新的前沿妊娠研究发展的第一个机制框架 在提供平移吸入输送的模型中，用于电子烟诱导的子宫循环适应 和与人类吸电子烟相当的蒸汽特征。建议研究电子烟对健康的影响， 怀孕将有助于实施有关这些设备对公众构成的潜在风险的适用政策。