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The effect of fetal programming on the expression of genes involved in adult vascular function

      Objective

      Endothelial nitric oxide synthase (NOS3) is involved in the vascular adaptations to pregnancy. We have previously reported that mice born to mothers lacking NOS3 gene have fetal growth abnormalities and abnormal vascular function in later life. This study investigate the potential mechanisms involved in the fetal programming of adult vascular function by evaluating expression of relevant genes in this animal model of fetal programming induced by an unfavorable uterine environment.

      Study design

      Homozygous NOS3 knockout (C57BL/6J-NOS3-/-KO) and wild type mice (NOS3+/+WT) were cross-bred to produce litters grown in a maternal environment lacking NOS3 (NOS3-/-KO] and maternally-heterozygous (NOS3+Pat/-Mat) and litters grown in normal maternal environment, paternally-derived heterozygous (NOS3+Mat/-Pat) and wild type (NOS3+/+WT). Female offspring at 7-8 weeks of age (n = 4-5/group) were sacrificed. The aorta was isolated and total RNA extracted. TaqMan and appropriate probes for neuronal (NOS1), inducible (NOS2), and cyclooxygenases 1 and 2 (COX1 and COX2), and for pre-developed 18S rRNA probe were used for real-time RT-PCR. mRNA quantification was expressed as relative value (ratio to its own 18s rRNA). One-way ANOVA followed by post-hoc test was used for statistical analysis.

      Results

      In the aorta, the NOS1, NOS2, and COX1 mRNA expressions were significantly lower in NOS3-/-KO and NOS3+Pat/-Mat female mice compared with NOS3+/+WT (P < .005). COX2 expression was not different between the groups (Table).

      Conclusion

      Fetal programming and altered vascular function in adult offspring developing in an unfavorable uterine environment are associated with downregulation of genes active in maintaining normal vascular function.
      Tabled 1Relative value
      NOS1NOS2COX1COX2
      NOS3-/-KO1.43 ± 0.0011.27 ± 0.011.16 ± 0.011.49 ± 0.002
      NOS3+Pat/-Mat1.35 ± 0.021.24 ± 0.0041.11 ± 0.0091.42 ± 0.01
      NOS3+Mat/-Pat1.49 ± 0.031.28 ± 0.0051.18 ± 0.011.40 ± 0.03
      NOS3+/+WT1.50 ± 0.031.30 ± 0.0051.23 ± 0.021.46 ± 0.02