Maternal inhaled nicotine leads to aberrant development of hypertensive phenotype

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Inhaled nicotine abuse either from tobacco cigarette or e-cigarette smoking is one of the most important risk factors in development of cardiovascular disease. Recent studies in women and animal models indicate that cigarette smoking or nicotine use by mothers during pregnancy increases the risk of hypertension and cardiovascular diseases in offspring. Oxidative stress has been implicated in the etiology of many diseases with substantial public health impact including chronic cardiovascular disorders and preeclampsia. Our recent studies in pregnant rats have demonstrated that perinatal nicotine exposure causes a development of vascular dysfunctional phenotype associated with an increased vascular specific NADPH oxidase (NOX2) gene expression and reactive oxygen species (ROS) production in adult offspring. However, the molecular mechanisms underlying nicotine-mediated programming of vascular oxidative stress are unclear. In addition, whether the heightened oxidative stress contributes to development of hypertensive phenotype remains undetermined. Recently, our research team has developed a non-invasive method delivering nicotine to rodents through inhalation with lung alveolar region-targeted aerosol technology (patent No. 61/418,304) that enables rapid delivery of adequate and controllable amount of nicotine into the circulation. This method closely resembles the route and both the arterial and venous blood nicotine kinetics of smoking a cigarette in human, and induces dose-dependent pharmacological effects in rodents. Our previous data show that chronic intermittent nicotine aerosol treatment (CINA) to rats produces circadian blood pharmacokinetics resembling chronic smokers. Therefore, in this proposed studies we will use the unique CINA pregnant rat model to test the central hypothesis that antenatal exposure to maternal inhaled nicotine programs vascular oxidative stress via epigenetic up-regulation of NOX2 gene, resulting in a hypertensive phenotype in offspring. Our working Specific Aim 1 will determine nicotine pharmacokinetics (PK) in CINA inhaled pregnant rats with our novel alveolar region-targeted aerosol technology and adjust the parameters of aerosol generation/exposure to simulate the PK of human chronic smokers. Specific Aim 2 will test the hypothesis that antenatal inhaled nicotine programs of vascular oxidative stress via epigenetic up-regulation of NOX2 expression. Specific Aim 3 will test the hypothesis that antenatal inhaled nicotine causes a development of hypertensive phenotype which is regulated by NOX2-related ROS signaling. The proposed studies will resolve whether maternal inhaled nicotine during pregnancy programs fetal oxidative stress and contributes to the development of hypertensive phenotype in adulthood. Innovative approaches in these studies provide the opportunity to identify epigenetic biomarkers during early life that have diagnostic and preventive value to the consequences of in utero adverse environmental exposure-induced cardiovascular disease in adulthood.