High oxygen prevents fetal lethality due to lack of catecholamines.
The catecholamine norepinephrine is required for fetal survival, but its essential function is unknown. When catecholamine-deficient [tyrosine hydroxylase (Th) null] mouse fetuses die at embryonic day (E)13.5-14.5, they resemble wild-type (wt) fetuses exposed to hypoxia. They exhibit bradycardia (28% reduction in heart rate), thin ventricular myocardium (20% reduction in tissue), epicardial detachment, and death with vascular congestion, hemorrhage, and edema. At E12.5, before the appearance of morphological deficits, catecholamine-deficient fetuses are preferentially killed by experimentally induced hypoxia and have lower tissue Po(2) levels than wt siblings. By microarray analysis (http://www.ncbi.nlm.nih.gov/geo; accession no. GSE10341), hypoxia-inducible factor-1 target genes are induced to a greater extent in null fetuses than in wt siblings, supporting the notion that mutants experience lower oxygen tension or have an enhanced response to hypoxia. Hypoxia induces a 13-fold increase in plasma norepinephrine levels, which would be expected to increase heart rate, thereby improving oxygen delivery in wt mice. Surprisingly, increasing maternal oxygen (inspired O(2) 33 or 63%) prevents the effects of catecholamine deficiency, restoring heart rate, myocardial tissue, and survival of Th null fetuses to wt levels. We suggest that norepinephrine mediates fetal survival by maintaining oxygen homeostasis.
Ream
Margie A
MA
Dept. of Neurobiology, Box 3209, Duke Univ. Medical Center, Durham, NC 27710, USA.
Chandra
Rashmi
R
Peavey
Mary
M
Ray
Alisa M
AM
Roffler-Tarlov
Suzanne
S
Kim
Hyung-Gun
HG
Wetsel
William C
WC
Rockman
Howard A
HA
Chikaraishi
Dona M
DM
D000818:Animals; D001919:Bradycardia / Q000401:mortality / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D005313:Fetal Death / Q000517:prevention & control; D018507:Gene Expression Regulation, Developmental; D006339:Heart Rate; D000860:Hypoxia / Q000401:mortality / Q000628:therapy*; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009638:Norepinephrine / Q000097:blood* / Q000172:deficiency; D010100:Oxygen / Q000494:pharmacology*; D010102:Oxygen Inhalation Therapy; D011247:Pregnancy; D015996:Survival Rate; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D014446:Tyrosine 3-Monooxygenase; D010100:Oxygen; D009638:Norepinephrine