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Maternal inhaled nicotine enhances endothelial nitric oxide synthase uncoupling leading to a hypertensive phenotype in offspring

Institution: Loma Linda University
Investigator(s): Bailin Liu,
Award Cycle: 2019 (Cycle 30) Grant #: T30FT0936 Award: $187,831
Subject Area: Cardiovascular and Cerebrovascular Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Fetal nicotine exposure, either from maternal smoking or nicotine use during pregnancy, has become a major public concern in modern life. Epidemiologic and experimental studies have shown that fetal nicotine exposure is associated with an increased risk of cardiovascular diseases in the postnatal life. However, the underlying molecular mechanisms remain unclear. In the vascular wall, an enzyme called as endothelial nitric oxide synthase (eNOS) can produce nitric oxide (NO) or superoxide anion (O2) dependent on the bioavailability of its cofactor tetrahydrobiopterin (BH4). If the vasculature system is undergoing BH4 deficiency, then the eNOS become uncoupling and the vasculature will produce much more O2 rather than NO. It is well known that endothelial derived NO induces vaso-relaxation. In contrast, endothelial derived O2 promotes vascular constriction. Thus, when eNOS is in the uncoupling stage, it could cause vascular constriction leading to a development of hypertensive phenotype. In this proposed project, we will employ a pregnant rat model with inhaled nicotine exposure during pregnancy. After prenatal inhaled nicotine (PIN) exposure, the offspring will be kept until adult age (~6 month old). Their blood pressure (BP) responses, vascular wall eNOS expression, and other factors will be determined and compared between the control and PIN exposed groups. We expect that PIN exposure will attenuate the arterial DNA methyltransferase expression level leading to reprogrammed vascular eNOS protein levels, which results in enhanced eNOS levels in the adult offspring. This progress will lead to eNOS uncoupling to produce less NO and more superoxide. Once this phenomenon occurs in their vascular walls, the offspring will develop hypertensive phenotype in their adult life. Therefore, the proposed studies provide novel evidence that children who are prenatally exposed to nicotine have much high risk of development of hypertensive phenotype in late life because the enzyme eNOS in their vascular wall has been epigenetically reprogrammed by the nicotine exposure. This project may lead to novel therapeutic approaches to prevent and treat the nicotine-mediated fetal origin of the cardiovascular disease.