RT Journal Article
SR Electronic
T1 Endothelial Dysfunction Abrogates the Efficacy of Normobaric Hyperoxia in Stroke
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 15200
OP 15207
DO 10.1523/JNEUROSCI.1110-14.2014
VO 34
IS 46
A1 Hwa Kyoung Shin
A1 Fumiaki Oka
A1 Ji Hyun Kim
A1 Dmitriy Atochin
A1 Paul L. Huang
A1 Cenk Ayata
YR 2014
UL http://www.jneurosci.org/content/34/46/15200.abstract
AB Hyperoxia has been uniformly efficacious in experimental focal cerebral ischemia. However, pilot clinical trials have showed mixed results slowing its translation in patient care. To explain the discordance between experimental and clinical outcomes, we tested the impact of endothelial dysfunction, exceedingly common in stroke patients but under-represented in experimental studies, on the neuroprotective efficacy of normobaric hyperoxia. We used hyperlipidemic apolipoprotein E knock-out and endothelial nitric oxide synthase knock-out mice as models of endothelial dysfunction, and examined the effects of normobaric hyperoxia on tissue perfusion and oxygenation using high-resolution combined laser speckle and multispectral reflectance imaging during distal middle cerebral artery occlusion. In normal wild-type mice, normobaric hyperoxia rapidly and significantly improved tissue perfusion and oxygenation, suppressed peri-infarct depolarizations, reduced infarct volumes, and improved neurological function. In contrast, normobaric hyperoxia worsened perfusion in ischemic brain and failed to reduce infarct volumes or improve neurological function in mice with endothelial dysfunction. These data suggest that the beneficial effects of hyperoxia on ischemic tissue oxygenation, perfusion, and outcome are critically dependent on endothelial nitric oxide synthase function. Therefore, vascular risk factors associated with endothelial dysfunction may predict normobaric hyperoxia nonresponders in ischemic stroke. These data may have implications for myocardial and systemic circulation as well.