Effect of chronic hypoxemia on the regulation of nitric-oxide synthase in the fetal sheep brain

We tested the hypothesis that chronic hypoxemia modulates NO production of the fetal brain by altering its gene and protein expression. Chronically in strumented preterm fetal sheep were made hypoxemic by placental embolizatio n for 21 days. Fetal oxygen content was measured to determine the level of hypoxemia. The expression of both eNOS and nNOS proteins and mRNA and enzym e activities of fetal sheep cerebrum were measured and compared between nor moxic and hypoxemic animals. Our results show that in utero hypoxemia downr egulates both Ca2+ dependent NOS activity and expression of eNOS protein an d mRNA in the fetal sheep brain. In contrast, hypoxemia increased nNOS prot ein and mRNA levels in the cerebrum. This suggests that chronic hypoxemia h as an opposing effect on eNOS and nNOS gene regulation. We propose that inc reased nNOS activity during chronic hypoxemia may excessively stimulate the neurons and contribute to fetal brain injury. On the other hand, downregul ation of eNOS activity and expression may compromise the neuroprotective ef fect of eNOS and, therefore, further exacerbate brain injury. (C) 1998 Else vier Science B.V. All rights reserved.