Hyperoxic exposure leads to nitrative stress and ensuing microvascular degeneration and diminished brain mass and function in the immature subject.
OBJECTIVE
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-kappaB 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.
Sirinyan
Mirna
M
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Sennlaub
Florian
F
Dorfman
Allison
A
Sapieha
Przemyslaw
P
Gobeil
Fernand
F
Hardy
Pierre
P
Lachapelle
Pierre
P
Chemtob
Sylvain
S
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology*; D008833:Microcirculation / Q000378:metabolism* / Q000473:pathology*; D009566:Nitrates / Q000378:metabolism*; D010100:Oxygen / Q000009:adverse effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009566:Nitrates; D010100:Oxygen