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 instrumented preterm fetal sheep were made hypoxemic by placental embolization 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 enzyme activities of fetal sheep cerebrum were measured and compared between normoxic and hypoxemic animals. Our results show that in utero hypoxemia downregulates both Ca2+ dependent NOS activity and expression of eNOS protein and mRNA in the fetal sheep brain. In contrast, hypoxemia increased nNOS protein and mRNA levels in the cerebrum. This suggests that chronic hypoxemia has an opposing effect on eNOS and nNOS gene regulation. We propose that increased nNOS activity during chronic hypoxemia may excessively stimulate the neurons and contribute to fetal brain injury. On the other hand, downregulation of eNOS activity and expression may compromise the neuroprotective effect of eNOS and, therefore, further exacerbate brain injury.
Aguan
K
K
Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore MD 21201, USA. kaguan@ummc001.ummc.ab.umd.edu
Murotsuki
J
J
Gagnon
R
R
Thompson
L P
LP
Weiner
C P
CP
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000196:embryology* / Q000201:enzymology*; D002118:Calcium / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology; D002908:Chronic Disease; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D000860:Hypoxia / Q000503:physiopathology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases; D012756:Sheep; D014158:Transcription, Genetic / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D012260:Ribonucleases; D002118:Calcium