Effect of chronic continuous or intermittent hypoxia and reoxygenation on cerebral capillary density and myelination

Abstract

Chronic hypoxia, whether continuous (CCH) or intermittent (CIH), occurs in many neonatal pathological conditions, such as bronchopulmonary dysplasia and obstructive sleep apnea. In this study, we explored the effect of CCH and CIH on cerebral capillary density and myelination. We subjected CD-1 mice starting at postnatal day 2 to either CCH 11% oxygen (O(2)), or CIH 11% O(2) (4-min cycles), for periods of 2 and 4 wk followed by reoxygenation for 4 wk. Mice were deeply anesthetized and perfused. Brains were removed to fixative for 24 h, then paraffin-embedded. Coronal brain sections were taken for analysis. Immunocytochemistry for glucose transporter 1 was used to assess angiogenesis, and Luxol fast blue and fluoromyelin stains were used to assess myelination. Capillary density increased after 2-wk exposure to CIH and CCH. By 4 wk, capillary density increased in both CIH and CCH by 25% and 47%, respectively, in cortex and by 29% and 44%, respectively, in hippocampus (P < 0.05). There was a decrease in myelination in the corpus callosum of mice exposed to CIH (75% of control) and CCH (50% of control) (P < 0.05). Reoxygenation reversed the increased capillary density seen in CCH to normoxic values. However, dysmyelination that occurred in CCH-exposed mice did not show any improvement upon reoxygenation. We conclude that neonatal chronic hypoxia 1) induces brain angiogenesis, which is reversible with reoxygenation, and 2) irreversibly reduces the extent of myelination in the corpus callosum. This potential irreversible effect on myelination in early life can, therefore, have long-term and devastating effects.

Differential effects of chronic intermittent and chronic constant hypoxia on postnatal growth and development

“…41,42 In fact, we have recently reported on dysmyelination and, more importantly, that this abnormal myelination was not reversible after reoxygenation. 35 It is also unknown if there is a difference in brain function after CIH as compared to CCH. Gozal and colleagues have argued in the past that CIH is more deleterious in terms of brain function since there is evidence of apoptosis and memory dysfunction after CIH as compared to CCH.…”

“…35 Briefly, P2 pups of mixed gender were housed with their own birth dams in isobaric chambers. A combination of nitrogen (N 2 ) and O 2 was injected into the chambers to achieve a final concentration of 11% oxygen.…”

“…[29][30][31][32][33][34] Hypoxia-induced gene regulation is rather well studied and such regulation can have long lasting effects. [29][30][31][32][33][34][35][36][37][38] There is a large body of literature on the effects of hypoxia on growth and that O 2 deprivation reduces body weight in animals in early life. 15,28,29 However, most of these studies have focused on a particular organ or they have not compared CCH and CIH as comprehensively as in the present study even though they suspect that CIH imposes oxidative stress in addition to its hypoxic effect.…”

Running, swimming and diving modifies neuroprotecting globins in the mammalian brain

“…Because the brain responds to hypoxia by transient increases in cerebral blood flow (Hudak et al 1986;Kanaan et al 2006), samples from prolonged mortality events (i.e. trauma and live stranding) were considered representative of a maximum, acute globin response in this study.…”

Prostaglandin transporter expression in mouse brain during development and in response to hypoxia

“…Food and water were provided ad libitum within the chamber. The protocols used to expose mice to hypoxia have been previously described (Douglas et al, 2003;Kanaan et al, 2006). In brief, a combination of nitrogen (N 2 ) and oxygen (O 2 ) was injected into the chambers through a network of tubing to achieve selected concentrations of O 2 .…”