Perinatal nicotine exposure increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: Role of angiotensin II receptors

BACKGROUND AND PURPOSE-: Maternal cigarette smoking increases the risk of neonatal morbidity. We tested the hypothesis that perinatal nicotine exposure causes heightened brain vulnerability to hypoxic-ischemic (HI) injury in neonatal rats through aberrant expression patterns of angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors in the developing brain. METHODS-: Nicotine was administered to pregnant rats through subcutaneous osmotic minipumps. HI brain injury was determined in 10-day-old pups. AT1R and AT2R expression patterns were assessed through Western blotting, quantitative polymerase chain reaction, immunofluorescence, and confocal imaging. RESULTS-: Perinatal nicotine exposure significantly increased HI brain infarct size in male, but not female, pups. In fetal brains, nicotine caused a decrease in mRNA and protein abundance of AT2R but not AT1R. The downregulation of AT2R persisted in brains of male pups, and nicotine treatment resulted in a significant increase in methylation of CpG locus 3 bases upstream of TATA-box at the AT2R gene promoter. In female brains, there was an increase in AT2R but a decrease in AT1R expression. Both AT1R and AT2R expressed in neurons but not in astrocytes in the cortex and hippocampus. Central application of AT1R antagonist losartan or AT2R antagonist PD123319 increased HI brain infarct size in both male and female pups. In male pups, AT2R agonist CGP42112 abrogated nicotine-induced increase in HI brain infarction. In females, PD123319 uncovered the nicotine's effect on HI brain infarction. CONCLUSION-: Perinatal nicotine exposure causes epigenetic repression of the AT2R gene in the developing brain resulting in heightened brain vulnerability to HI injury in neonatal male rats in a sex-dependent manner. © 2012 American Heart Association, Inc.