Submitted on December 1, 2007
Accepted on July 3, 2008
High oxygen prevents fetal lethality due to lack of catecholamines
Margie Ann Ream1, Rashmi Chandra1, Mary Peavey1, Alisa M Ray1, Suzanne K Roffler-Tarlov2, Hyung-Gun Kim3, William C Wetsel3, Howard A Rockman4, and Dona M Chikaraishi1*
1 Neurobiology, Duke University Medical Center, Durham, North Carolina, United States
2 Neuroscience, Tufts University Medical Center, Boston, Massachusetts, United States
3 Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States
4 Medicine, Division of Cardiovascular Medicine, Duke University Medical Center, Durham, North Carolina, United States
* To whom correspondence should be addressed. E-mail: donam{at}neuro.duke.edu.
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 E13.5-E14.5, they resemble wild type 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, prior to the appearance of morphological deficits, catecholamine-deficient fetuses are preferentially killed by experimentally-induced hypoxia and have lower tissue PO2 levels than wild type siblings. By microarray analysis (http://www.ncbi.nlm.nih.gov/geo, series record GSE10241), HIF-1 target genes are induced to a greater extent in null fetuses than in wild type 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 wild type mice. Surprisingly, increasing maternal oxygen (FiO2 33% or 63%) prevents the effects of catecholamine-deficiency, restoring heart rate, myocardial tissue and survival of Th null fetuses to wild type levels. We suggest that norepinephrine mediates fetal survival by maintaining oxygen homeostasis.
