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Prenatal Nicotine Exposure and Vascular Programming

Institution: Loma Linda University
Investigator(s): DaLiao Xiao, Ph.D.
Award Cycle: 2009 (Cycle 18) Grant #: 18KT-0024 Award: $289,840
Subject Area: Nicotine Dependence
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
Maternal cigarette smoking is the single most widespread prenatal insult in the world. It is likely to become of even greater significance with the increasing use of tobacco in Third World countries that have typically high pregnancy rates. However, despite extensive adverse publicity, approximately 25% of all women in the United States continue to smoke during pregnancy, overshadowing illicit drugs of abuse. 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 epidemiological studies: tens of thousands of spontaneous abortions and neonatal intensive care unit admissions annually, thousands of perinatal deaths and deaths from Sudden Infant Death Syndrome (SIDS) and substantially increased risk of learning disabilities, behavioral problems and attention deficit and hyperactivity disorder. Maternal smoking produces, at least, two major different families of potential effects: actions of nicotine in the fetus, whether on brain development or general development; actions on the maternal-fetal unit, including episodic hypoxia-ischemia, and affecting the uteroplancental circulation.

Our current studies are focusing on the effect of smoking/nicotine on the fetal development. Recently, we have demonstrated that in utero exposure to nicotine impaired cardiovascular function in adult rat offspring. Moreover, our preliminary data indicated that maternal nicotine exposure cause an increase in blood pressure responses in adult male but not female rat offspring. This exciting novel finding suggests that smoking during pregnancy may exert a direct affect on fetal development and lead to an increased risk of hypertension in the offspring later in life. The major goal of this project is to explore the cellular/molecular mechanisms underlying prenatal nicotine exposure-associated changes in blood pressure, and how nicotine exposure during pregnancy causes certain gene expression reprogramming and it mediated signaling pathways, which lead to increase vascular resistance and increases susceptibility of elevated blood pressure in the offspring. We also want to know why this effect only occurs in male but not in female offspring.

The proposed studies will provide new and direct evidence that mother smoking during pregnancy will increase the risk of hypertension/cardiovascular disease in her children hood or adulthood. Our studies will provide a mechanistic link between adverse intrauterine environments and fetal programming resulting in an increase the risk of hypertension and cardiovascular disease in adulthood. Understanding of the mechanisms in the adaptation of vascular contractility in response to nicotine exposure is fundamental physiologic importance in its own right, as well as having considerable clinical relevance. They will help to provide several possible approaches to improve vascular function, and to reduce high blood pressure in the clinical situation.
Publications

Pregnancy downregulates actin polymerization and pressuredependent_x000D_ myogenic tone
Periodical: Hypertension Index Medicus:
Authors: Xiao D, Huang X, Yang S, Longo LD, Zhang L. ART
Yr: 2010 Vol: Nbr: Abs: Pg: 1009-1015

Role of KATP and L-type Ca2+ channel activities in regulation of ovine uterine_x000D_ vascular contractility; effect of pregnancy and chronic hypoxia
Periodical: American Journal of Obstetrics and Gynecology Index Medicus:
Authors: Xiao D, Longo LD, Zhang L. ART
Yr: 2010 Vol: Nbr: 203 Abs: Pg: 596-601

Fetal nicotine exposure causes PKO: gene repression by promoter methylation in the heal1
Periodical: Cardiovascular Research Index Medicus:
Authors: Lawrence J, Chen M, Xiao D, Zhang H, Buchholz IN, Zhang L. ART
Yr: 2011 Vol: Nbr: 89 Abs: 2011 Pg: 89-97

Antenatal Nicotine Induces Heightened Oxidative Stress and_x000D_ Vascular Dysfunction in Rat Offspring.
Periodical: British Journal of Pharmacology Index Medicus:
Authors: Xiao D, Huang XH, Yang S, Zhang L. ART
Yr: 2011 Vol: Nbr: 164 Abs: Pg: 1400-1409

Hypoxia-derived oxidative stress mediated epigenetic repression ofPKC{avrepsion} gene in fetal rat hearts
Periodical: Cardiovascular Research Index Medicus:
Authors: Patterson Al, Xiao D, Xiong F, Dixon B, Zhang L. ART
Yr: 2012 Vol: Nbr: 93 Abs: Pg: 302-310

Norepinephrine causes epigenetic repression of PKC{varepsilon} gene in rodent hearts by activating NOXl-dependent reactive oxygen species production
Periodical: FASEB Journal Index Medicus:
Authors: Xiong F, Xiao D, Zhang 1. ART
Yr: 2012 Vol: Nbr: Abs: Pg:

Developmental nicotine exposure results in programming of_x000D_ alveolar simplification and interstitial pulmonary fibrosis in adult male rats
Periodical: Reproductive Toxicology Index Medicus:
Authors: Dasgupta C, Xiao D, Xu Z, Yang S, Zhang L. ART
Yr: Vol: Nbr: 34 Abs: Pg: 370-377

Perinatal nicotine exposure increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: role of angiotensin If receptor
Periodical: Stroke Index Medicus:
Authors: Li Y, Xiao D, Dasgupta C, Xiong F, Tong W, Yang S, Zhang L. ART
Yr: 2012 Vol: Nbr: 43 Abs: Pg: 2483-90