Research Project
10459954
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.
