title: High oxygen prevents fetal lethality due to lack of catecholamines.
abstract: 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.
authors.affiliation: Dept. of Neurobiology, Box 3209, Duke Univ. Medical Center, Durham, NC 27710, USA.
authors.forename: Margie A
authors.initials: MA
authors.lastname: Ream
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chandra
authors.forename: Mary
authors.initials: M
authors.lastname: Peavey
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Ray
authors.forename: Suzanne
authors.initials: S
authors.lastname: Roffler-Tarlov
authors.forename: Hyung-Gun
authors.initials: HG
authors.lastname: Kim
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
authors.forename: Dona M
authors.initials: DM
authors.lastname: Chikaraishi
mesh_terms: 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
chemical_list: D051793:Hypoxia-Inducible Factor 1; D014446:Tyrosine 3-Monooxygenase; D010100:Oxygen; D009638:Norepinephrine