The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development.
Mice lacking the hypoxia-inducible transcription factor EPAS1 die at mid-gestation. Despite normal morphological development of the circulatory system, EPAS1-deficient mice display pronounced bradycardia. In addition to the vascular endothelium, EPAS1 is expressed intensively in the organ of Zuckerkandl (OZ), the principle source of catecholamine production in mammalian embryos. EPAS1-deficient embryos contained substantially reduced catecholamine levels. Mid-gestational lethality was rescued by administration of the catecholamine precursor DOPS to pregnant females. We hypothesize that EPAS1 expressed in the OZ senses hypoxia during mid-gestational development and translates this signal into an altered pattern of gene expression, leading to increases in circulating catecholamine levels and proper cardiac function.
Tian
H
H
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235 USA.
Hammer
R E
RE
Matsumoto
A M
AM
Russell
D W
DW
McKnight
S L
SL
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002395:Catecholamines / Q000378:metabolism / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000235:genetics*; D006333:Heart Failure / Q000196:embryology* / Q000235:genetics; D018257:Helix-Loop-Helix Motifs / Q000235:genetics; D006706:Homeostasis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D002395:Catecholamines; D015534:Trans-Activators; D000099162:Endothelial PAS Domain-Containing Protein 1