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 via 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 via subcutaneous osmotic minipumps. HI brain injury was determined in 10-day-old pups. AT1R and AT2R expression patterns were assessed via Western blotting, q-PCR, 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 three bases upstream of TATA-box at 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 AT2R gene in the developing brain resulting in heightened brain vulnerability to HI injury in neonatal male rats in a sex-dependent manner.

Tong W, Xue Q, Li Y, Zhang L. Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats. Am J Physiol Heart Circ Physiol 301: H2113-H2121, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00356.2011.-Fetal hypoxia leads to progressive cardiac remodeling in rat offspring. The present study tested the hypothesis that maternal hypoxia results in reprogramming of matrix metalloproteinase (MMP) expression patterns and fibrillar collagen matrix in the developing heart. Pregnant rats were treated with normoxia or hypoxia (10.5% O2) from day 15 to 21 of gestation. Hearts were isolated from 21-day fetuses (E21) and postnatal day 7 pups (PD7). Maternal hypoxia caused a decrease in the body weight of both E21 and PD7. The heart-to-body weight ratio was increased in E21 but not in PD7. Left ventricular myocardium wall thickness and cardiomyocyte proliferation were significantly decreased in both fetal and neonatal hearts. Hypoxia had no effect on fibrillar collagen content in the fetal heart, but significantly increased the collagen content in the neonatal heart. Western blotting revealed that maternal hypoxia significantly increased collagen I, but not collagen III, levels in the neonatal heart. Maternal hypoxia decreased MMP-1 but increased MMP-13 and membrane type (MT)1-MMP in the fetal heart. In the neonatal heart, MMP-1 and MMP-13 were significantly increased. Active MMP-2 and MMP-9 levels and activities were not altered in either fetal or neonatal hearts. Hypoxia significantly increased tissue inhibitors of metalloproteinase (TIMP)-3 and TIMP-4 in both fetal and neonatal hearts. In contrast, TIMP-1 and TIMP-2 were not affected. The results demonstrate that in utero hypoxia reprograms the expression patterns of MMPs and TIMPs and causes cardiac tissue remodeling with the increased collagen deposition in the developing heart.

Introduction-Surgical brain injury (SBI) is unavoidable during many neurosurgical procedures. This inevitable brain injury can result in postoperative complications including brain edema, bloodbrain barrier disruption (BBB) and cell death in susceptible areas. Rosiglitazone (RSG), a PPAR-γ agonist, has been shown to reduce inflammation and provide neuroprotection in experimental models of ischemia and intracerebral hemorrhage. This study was designed to evaluate the neuroprotective effects of RSG in a rodent model of SBI.Methods-65 adult male Sprague-Dawley rats were randomly divided into sham, vehicle and treatment groups. RSG was administered intraperitoneally in two dosages (1mg/kg/dose, 6mg/kg/ dose) 30 minutes before surgery, and 30 minutes and 4 hours after surgery. Animals were euthanized 24 hrs following neurological evaluation to assess brain edema and BBB permeability by IgG staining. Inflammation was examined using myeloperoxidase (MPO) assay and double-labeling fluorescent immunohistochemical analysis of IL-1β and TNF-α.Results-Localized brain edema was observed in tissue surrounding the surgical injury. This brain edema was significantly higher in rats subjected to SBI than sham animals. Increased IgG staining was present in affected brain tissue; however, RSG reduced neither IgG staining nor brain edema. RSG also did not improve neurological status observed after SBI. RSG, however, significantly attenuated MPO activity and qualitatively decreased IL-1β and TNF-α expression compared to vehicle-treated group.Conclusion-SBI causes increased brain edema, BBB disruption and inflammation localized along the periphery of the site of surgical resection. RSG attenuated inflammatory changes, however, did not improve brain edema, BBB disruption and neurological outcomes after SBI.