Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier.
OBJECTIVE
The blood-brain barrier (BBB) is a selectively permeable cerebrovascular endothelial barrier that maintains homeostasis between the periphery and the central nervous system. BBB disruption is a consequence of ischemic stroke and BBB permeability can be altered by infection/inflammation, but the complex cellular and molecular changes that result in this BBB alteration need to be elucidated to determine mechanisms.


METHODS
Infection mimic (lipopolysaccharide) challenge on infarct volume, BBB permeability, infiltrated neutrophils, and functional outcomes after murine transient middle cerebral artery occlusion in vivo; mitochondrial evaluation of cerebrovascular endothelial cells challenged by lipopolysaccharide in vitro; pharmacological inhibition of mitochondria on BBB permeability in vitro and in vivo; the effects of mitochondrial inhibitor on BBB permeability, infarct volume, and functional outcomes after transient middle cerebral artery occlusion.


RESULTS
We report here that lipopolysaccharide worsens ischemic stroke outcome and increases BBB permeability after transient middle cerebral artery occlusion in mice. Furthermore, we elucidate a novel mechanism that compromised mitochondrial function accounts for increased BBB permeability as evidenced by: lipopolysaccharide-induced reductions in oxidative phosphorylation and subunit expression of respiratory chain complexes in cerebrovascular endothelial cells, a compromised BBB permeability induced by pharmacological inhibition of mitochondrial function in cerebrovascular endothelial cells in vitro and in an in vivo animal model, and worsened stroke outcomes in transient middle cerebral artery occlusion mice after inhibition of mitochondrial function.


CONCLUSIONS
We concluded that mitochondria are key players in BBB permeability. These novel findings suggest a potential new therapeutic strategy for ischemic stroke by endothelial cell mitochondrial regulation.
From the Department of Neurobiology and Anatomy (D.N.D.), Experimental Stroke Core, Center for Basic and Translational Stroke Research (H.H., S.E.L., J.W.S., X.R.), and Department of Physiology and Pharmacology (H.H., J.S., S.E.L., J.W.S., X.R.), West Virginia University, Morgantown.
Danielle N
DN
Doll
From the Department of Neurobiology and Anatomy (D.N.D.), Experimental Stroke Core, Center for Basic and Translational Stroke Research (H.H., S.E.L., J.W.S., X.R.), and Department of Physiology and Pharmacology (H.H., J.S., S.E.L., J.W.S., X.R.), West Virginia University, Morgantown.
Heng
H
Hu
From the Department of Neurobiology and Anatomy (D.N.D.), Experimental Stroke Core, Center for Basic and Translational Stroke Research (H.H., S.E.L., J.W.S., X.R.), and Department of Physiology and Pharmacology (H.H., J.S., S.E.L., J.W.S., X.R.), West Virginia University, Morgantown.
Jiahong
J
Sun
From the Department of Neurobiology and Anatomy (D.N.D.), Experimental Stroke Core, Center for Basic and Translational Stroke Research (H.H., S.E.L., J.W.S., X.R.), and Department of Physiology and Pharmacology (H.H., J.S., S.E.L., J.W.S., X.R.), West Virginia University, Morgantown.
Sara E
SE
Lewis
From the Department of Neurobiology and Anatomy (D.N.D.), Experimental Stroke Core, Center for Basic and Translational Stroke Research (H.H., S.E.L., J.W.S., X.R.), and Department of Physiology and Pharmacology (H.H., J.S., S.E.L., J.W.S., X.R.), West Virginia University, Morgantown.
James W
JW
Simpkins
From the Department of Neurobiology and Anatomy (D.N.D.), Experimental Stroke Core, Center for Basic and Translational Stroke Research (H.H., S.E.L., J.W.S., X.R.), and Department of Physiology and Pharmacology (H.H., J.S., S.E.L., J.W.S., X.R.), West Virginia University, Morgantown. xuren@hsc.wvu.edu.
Xuefang
X
Ren
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability; D004579:Electron Transport / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D020521:Stroke / Q000378:metabolism* / Q000473:pathology
D008070:Lipopolysaccharides
blood-brain barrier; mitochondria; stroke