Hyperoxic Exposure Leads to Nitrative Stress and Ensuing Microvascular Degeneration and Diminished Brain Mass and Function in the Immature Subject
- 1 November 2006
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Stroke
- Vol. 37 (11), 2807-2815
- https://doi.org/10.1161/01.str.0000245082.19294.ff
Abstract
Background and Purpose— Neonates that survive very preterm birth have a high prevalence of cognitive impairment in later life. A common factor detected in premature infants is their postnatal exposure to high oxygen tension relative to that in utero. Hyperoxia is known to elicit injury to premature lung and retina. Because data on the exposure of the brain to hyperoxia are limited, we studied the effects of high oxygen on this tissue. Methods— Rat pups were exposed from birth until day 6 to 21% or 80% O 2 . Cerebral vascular density was quantified by lectin immunohistochemistry. Immunoblots for several proteins were performed on brain extracts. We assessed cerebral functional deficits by visual evoked potentials. Results— Exposure of pups to hyperoxia leads to cerebral microvascular degeneration, diminished brain mass, and cerebral functional deficits. These effects are preceded by an upregulation of endothelial nitric oxide synthase (eNOS) in cerebral capillaries and a downregulation of Cu/Zn superoxide dismutase (SOD). The imbalance in nitric oxide (NO) production and antioxidant defenses favors the formation of nitrating agents in the microvessels revealed by increased nitrotyrosine (3-nt) immunoreactivity and decreased expression of NF-κB and the dependent vascular endothelial growth factor receptor 2. NOS inhibitors and eNOS deletion as well as an SOD mimetic (CuDIPS) restore vascular endothelial growth factor receptor-2 levels and nearly abolish the vasoobliteration. NOS inhibitors and SOD mimetic also prevent O 2 -induced diminished brain mass and functional deficit. Conclusions— Data identify NO and nitrating agents as major mediators of cerebral microvascular damage, ensuing impaired brain development and function in immature subjects exposed to hyperoxia.Keywords
This publication has 29 references indexed in Scilit:
- Early Brain Injury in Premature Newborns Detected with Magnetic Resonance Imaging is Associated with Adverse Early Neurodevelopmental OutcomeThe Journal of Pediatrics, 2005
- Changes in Neurodevelopmental Outcomes at 18 to 22 Months' Corrected Age Among Infants of Less Than 25 Weeks' Gestational Age Born in 1993–1999Pediatrics, 2005
- The Unexpected Brains Behind Blood Vessel GrowthScience, 2005
- Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitrationJournal of Cell Science, 2005
- Redox-dependent effects of nitric oxide on microvascular integrity in oxygen-induced retinopathyFree Radical Biology & Medicine, 2004
- Contributions of Endothelial and Neuronal Nitric Oxide Synthases to Cerebrovascular Responses to HyperoxiaJournal of Cerebral Blood Flow & Metabolism, 2003
- Transient Elevation of Glutathione Peroxidase 1 Around the Time of Eyelid Opening in the Neonatal RatJournal of Ocular Pharmacology and Therapeutics, 2003
- Inducible nitric oxide synthase mediates the change from retinal to vitreal neovascularization in ischemic retinopathyJCI Insight, 2001
- Manganese ad copper-zinc superoxide dismutases in the developing rat retinaActa Histochemica, 1997
- The Differential Diagnosis of Protein-Energy Malnutrition: Implications for PreventionProceedings Of The Nutrition Society, 1979