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This Article Full Text Full Text (PDF) Supplemental Figures and Tables All Versions of this Article: 295/3/R942    most recent 00860.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ream, M. A. Articles by Chikaraishi, D. M. Search for Related Content PubMed PubMed Citation Articles by Ream, M. A. Articles by Chikaraishi, D. M.

EXERCISE AND RESPIRATORY PHYSIOLOGY

High oxygen prevents fetal lethality due to lack of catecholamines

¹Department of Neurobiology, Duke University Medical Center, Durham, North Carolina; ²Department of Neuroscience, Tufts University Medical Center, Boston, Massachusetts; and ³Department of Psychiatry and Behavioral Sciences, ⁴Department of Cell Biology, and Divisions of ⁵Endocrinology and ⁶Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina

Submitted 1 December 2007 ; accepted in final form 3 July 2008

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 PO₂ 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 O₂ 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.

hypoxia; fetal stress; thin myocardium; bradycardia; norepinephrine