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

电子烟

基本信息

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
项目类别：
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

项目摘要

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.

怀孕期间子宫中的电子香烟蒸发和血管后遗症尽管怀孕严重并发症，使用烟草产品的女性中有50％继续进行因此在怀孕期间。 2017年最近的一项研究估计，许多妇女使用电子烟（E-cigs）作为怀孕期间的常规香烟。这种令人震惊的数据的主要原因是传统烟草用户将怀孕期间的VAP视为“更安全”的替代方案。但是，e-cig蒸气揭示了无数的可能对母亲和胎儿有害的化学物质。使用我们成熟的怀孕大鼠模型，我们获得了最先进的初步数据定制设计的电子烟雾化器提供了翻译的吸入输送方法并产生的蒸气剖面直接与人类烟相媲美。初步数据证明了电子烟引起的主要胎儿生长不足，并为妊娠电路适应受损提供了第一个证据血流，天然气和养分从母亲到胎儿的主要调节因子。 AIM＃1将测试是否蒸发电子烟碱（丙二醇：甘油（80:20））或增加剂量增加的尼古丁产生剂量依赖性对子宫血流（UBF）和胎儿生长反应的影响。此外，我们将测试是否存在电子烟怀孕期间的全身心血管适应。我们将评估生殖血管和全身性单独或使用高频剂量增加尼古丁的心血管适应超声检查，TTE，ECG，Luminex XMAP技术，血压外科导管插入术和基于微球的流量评估。 AIM＃2将测试Vaping E-cig是否会通过内皮衍生的无与EDHF与PGI2途径（完全调节主要的三个血管扩张剂子宫动脉血流在怀孕时）。我们将实际阻止内皮衍生的组合使用压力动脉造影的血管扩张途径，并使用HPLC解剖细胞信号传导，组织学方法，免疫印迹和其他分子工具。 AIM＃3将测试是否重新计算电子烟 - 在不存在电子烟的情况下，诱导的UBF降低会产生胎儿生长限制，如果恢复电子烟 - 受损的UBF反应了经电子烟治疗的动物的生长限制表型。我们将使用表仿 RNA干扰介导的抑制内皮依赖性血管舒张的mRNA转录本在没有电子烟蒸发的情况下，介体和重新创建的E-cig引起的UBF下降。使用慢病毒表达转换以恢复UBF，我们将确定是否可以挽救生长限制表型电子烟治疗的动物。我们的建议探讨了妊娠研究的新领域，开发了第一个机械框架用于E-CIG蒸发引起的子宫回路适应，以提供转化吸入输送和蒸气曲线可与人类雾化相提并论。提出的关于电子烟的健康影响的研究怀孕将促进这些设备对公众构成潜在风险的适用政策实施。