Hyperoxia Induced Hypomyelination

• Published in: Biomedicines Vol. 11; no. 1; p. 37
• Main Authors: Song, Weilin, Hoppe, George, Hanna, Demiana, DeSilva, Tara M, Sears, Jonathan E
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.12.2022; MDPI
• Subjects: Apoptosis; Birth weight; Capillaries; Corpus callosum; Fibrosis; Glial fibrillary acidic protein; Hyperoxia; Hypoxia; hypoxia inducible factor; Immunofluorescence; Immunohistochemistry; Infants; Ischemia; Laboratories; Liver; Mortality; Myelin basic protein; Myelination; Neonates; Oligodendrocytes; Pathogenesis; Periventricular leukomalacia; Premature babies; Premature birth; Protocol; Traumatic brain injury; Vascular endothelial growth factor; United States > US; periventricular leukomalacia; premature birth; hyperoxia; HIF stabilization; prolyl hydroxylase; hypoxia inducible factor; oligodendrocytes; hypomyelination; myelin basic protein
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines11010037

We asked whether hyperoxia might induce hypomyelination of the corpus callosum, clinically described as periventricular leukomalacia (PVL) of the severely preterm infant. Mouse pups and their nursing dams were placed in 80% oxygen from P4-P8, then removed to room air until P11. Corpus callosal sections were probed myelin immunofluorescence, tested for myelin basic protein concentration by Western blot, and both glial fibrillary acidic protein levels and apoptosis quantified. Density of corpus callosal capillaries were measured after lectin staining and hypoxia measured by Hypoxyprobe. Numbers of oligodendrocytes were quantified by immunohistochemistry. We next used hypoxiamimesis as a surrogate to hypoxia by comparing cerebral hypoxia inducible factor (HIF) stabilization to hepatic HIF stabilization. Hyperoxia induced hypomyelination and a reduction of corpus callosal capillaries. Hyperoxia decreased numbers of oligodendrocytes with an increase in corpus callosal fibrosis and apoptosis. Cerebral hypoxiamimesis induced hypomyelination whereas hepatic hypoxiamimesis alone increased myelination, oligodendrocyte numbers, and corpus callosal capillary density. Hepatic HIF-1 dependence on myelination was confirmed using the cre/lox hepatic HIF-1 knockout. These findings suggest that hyperoxia can induce hypomyelination through vasoobliteration and subsequent ischemia, adding a potential oxygen induced mechanism to the diverse causes of periventricular leukomalacia of the severely preterm infant. Targeting hepatic HIF-1 alone led to increased myelination.