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Nicotine's effects on uterine artery contractillity

Institution: Loma Linda University
Investigator(s): DaLiao Xiao,
Award Cycle: 2005 (Cycle 14) Grant #: 14FT-0075 Award: $73,878
Subject Area: Nicotine Dependence
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Cigarette smoking among women during pregnancy continues to be a major health concern. Despite decades of adverse publicity, approximately 25% of all women in the United States continue to smoke during pregnancy. Smoking has long been associated with adverse pregnancy outcomes, both for the mother, her fetus, and her newborn. The consequences have been well identified in underweight newborns, in high rates of perinatal mortality and Sudden Infant Death Syndrome and in persistent deficits in learning and behavior in offspring. Smoking/nicotine has a profound effect on uterine blood flow during pregnancy of women and animals, which, at least, partly contribute to those detrimental effects on the developing fetus.Uterine artery is the only source to deliver oxygen and nutrition to the developing fetus. The precise regulation of uterine blood flow during pregnancy is important not only for the growth and survival of the fetus but also for cardiovascular well-being of the mother. Any perturbation of this system can affect not only the growth and survival of the fetus but also cardiovascular well-being of their mother. Our preliminary in vitro studies indicated that contractile sensitivity of the ovine pregnant uterine artery to a1-adrenoceptor stimulation was significantly enhanced with the treatment of nicotine. Yet the cellular/molecular mechanisms underlying the effect of nicotine on uterine artery contractility are not understood. The proposed studies focus on these mechanisms. The main hypothesis is that nicotine influences pregnancy-induced vascular adjustment of the uterine artery by depressing endothelial function, and enhancing smooth muscle pharmacomechanical coupling. To test this hypothesis, we propose a series of experiments in the uterine arteries from near-term (~140 days) pregnant and nonpregnant sheep. Our specific aims are to determine whether: 1) nicotine down-regulates endothelial nitric oxide synthase (eNOS) activity and gene expression in the uterine artery; 2) nicotine enhances pharmacomechanical coupling of a1-adrenergic receptors in the uterine artery; 3) nicotine enhances protein kinase C (PKC) signaling pathway-mediated contraction in the uterine artery.The results of the proposed studies will provide important original insights into biochemical, cellular, and path-physiologic adaptive mechanisms involved in adjusting uteroplacental circulation in response to nicotine exposure. Understanding of the mechanisms in the regulation of uterine blood flow in response to nicotine exposure is fundamental physiologic importance in its own right, as well as having considerable clinical relevance. Given the important role of uterine blood flow in fetal development and maternal health, failure to make these adjustments may contribute to many fetal abnormalities, including intrauterine growth restriction, as well as maternal cardiovascular disorders associated with nicotine exposure. The proposed studies will help provide a mechanistic basis for this functional adaptation, and thereby improve our understanding of problems associated with the maladaptation and abnormal pregnancy and permit us to address them in a more meaningful way.