Prolonged mild fetal hypoxia up-regulates type I nitric oxide synthase expression in discrete areas of the late-gestation fetal sheep brain.

Objective: Our purpose was to study the effects of prolonged mild hypoxemia on type I nitric oxide synthase (NOS) messenger RNA, protein, and enzymatic activity in the fetal sheep brain.

Study Design: Pregnant sheep were randomly allocated to receive maternal nitrogen (n = 8) or compressed air (controls, n = 5) to reduce fetal brachial artery PO(2) by 25% for 5 days. Type I NOS mRNA (determined by ribonuclease protection assay) protein (determined by Western blot) and enzymatic activity (determined by citrulline assay) were measured in the hippocampus, striatum, cerebellum, and frontal cortex. Data are presented as mean +/- SEM and were compared by means of one-way analysis of variance or two-sample t test.

Results: The reduction in maternal inspired oxygen concentration decreased fetal PO(2) by 26% and oxygen content by 25% without an associated change in PCO(2) or pH. Fetal hypoxemia increased type I NOS mRNA by threefold in the striatum and by 2-fold in the frontal cortex and cerebellum, but it did not change mRNA expression in the hippocampus (P <.05). Type I NOS protein and catalytic activity increased only in the striatum (P <.05).

Conclusion: Prolonged mild hypoxemia has a differential effect on type I NOS mRNA in fetal sheep brain areas. Type I NOS protein and catalytic activity significantly increased only in the striatum. Our data suggest that fetal type I NOS gene expression is regulated at transcriptional, post-transcriptional, and translational levels.