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

电子烟蒸发与妊娠期子宫血管后遗症 尽管有严重的妊娠并发症，50%使用烟草产品的女性仍将继续 所以在怀孕期间。最近2017年的一项研究估计，使用电子烟(电子烟)的女性人数与 怀孕期间的常规香烟。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，电子烟蒸气显示出无数的 可能对母亲和胎儿都有害的化学物质。 使用我们建立的怀孕大鼠模型，我们利用最先进的技术获得了初步数据 定制设计的e-cig雾化器，提供平移吸入输送方法并产生蒸汽 可直接与人体蒸发相媲美。初步数据显示，e-cig诱导的主要胎儿 生长缺陷，并为包括子宫在内的妊娠循环适应受损提供了第一个证据 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将测试蒸发电子烟是否 基础(丙二醇：甘油(80：20))单独或随着尼古丁剂量的增加产生剂量依赖关系 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由电子烟引起的 妊娠期间的全身心血管适应。我们将评估生殖血管和系统 单独使用e-CIG或使用高频尼古丁剂量增加时的心血管适应性 超声波、TTE、心电、Luminex xMAP技术、外科血压插管，以及 基于微球的流动评估。目标2将测试蒸发e-cig是否会通过 内皮来源的NO、EDHF和PGI2途径(三种完全调节初级血管的血管扩张剂 妊娠期子宫动脉血流量)。我们将从药物上阻止内皮细胞衍生的组合 血管扩张途径使用压力动脉造影术，并使用高效液相色谱剖析受损细胞信号， 组织学方法、免疫印迹和其他分子工具。目标3将测试重新投降的电子烟- 在没有e-cig的情况下，诱导的UBF降低会导致胎儿生长受限，如果恢复e-cig- 受损-UBF挽救了e-CIG处理的动物的生长限制表型。我们将使用表型复制 RNA干扰抑制内皮依赖性血管舒张剂的mRNA转录 在没有电子CIG蒸发的情况下，重新创建电子CIG导致的UBF下降。使用慢病毒 表达转基因(S)修复UBF，我们将确定这是否可以挽救生长受限表型 接受电子烟处理的动物。 我们的建议探索了孕育研究的新前沿，开发了第一个机械框架 在提供平移吸入的模型中，用于e-cig汽化诱导的子宫循环适应 以及类似于人体蒸发的蒸气轮廓。关于电子烟对健康影响的拟议研究 怀孕将有助于就这些设备对公众构成的潜在风险执行适用的政策。

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.