Placental HIFs as markers of cerebral hypoxic distress in fetal mice.
Reduced oxygen supply during the pre- and perinatal period often leads to acquired neonatal brain damage. So far, there are no reliable markers available to assess the hypoxic cerebral damage and the resulting prognosis during the immediate postnatal period. Thus we aimed to determine whether the hypoxia-inducible transcription factors (HIF-1 and HIF-2) and/or their target genes in the placenta represent reliable indicators of hypoxic distress of the developing brain during systemic hypoxia at the end of gestation. To this end, pregnant mice were exposed to systemic hypoxia (inspired O2 fraction: 6%, 6 h) at gestational day 20. This hypoxic exposure significantly increased HIF-1alpha and HIF-2alpha protein levels in brain and placental tissue. Compared with normoxic controls, an increase of HIF-1alpha-immunoreactive neurons and HIF-2alpha-positive glial cells and vascular endothelial cells was observed in hypoxic cerebral cortex and hippocampus. In placenta, HIF-1alpha and HIF-2alpha were expressed in labyrinthine layer with increased staining intensity during hypoxia compared with normoxia. Significant upregulation of VEGF mRNA and protein in brain and placenta, as well as erythropoietin protein in placenta, indicated activity of the HIF system upon fetal hypoxia. Notably, hypoxia did not affect expression of the HIF target genes inducible nitric oxide synthase and GLUT-1. Taken together, at gestational day 20, systemic hypoxia led to upregulation of HIF-alpha in mouse brain that was temporally paralleled in placenta, implying that alpha-subunits of both HIF-1 and HIF-2 are indeed early markers of hypoxic distress in vivo. If our data reflect the situation in humans, analysis of the placenta will allow early identification of the hypoxic brain distress occurring near birth.
Trollmann
Regina
R
Department of Pediatrics, University of Erlangen, Erlangen, Germany.
Strasser
Katja
K
Keller
Stephan
S
Antoniou
Xenia
X
Grenacher
Beat
B
Ogunshola
Omolara O
OO
Dötsch
Jörg
J
Rascher
Wolfgang
W
Gassmann
Max
M
D000208:Acute Disease; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005311:Fetal Hypoxia / Q000378:metabolism*; D005786:Gene Expression Regulation; D005865:Gestational Age; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D002534:Hypoxia, Brain / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D055550:Protein Stability; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D004921:Erythropoietin; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C495678:Slc2a1 protein, mouse; C467480:vascular endothelial growth factor A, mouse; C496317:Nos2 protein, mouse