Title

Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier

Document Type

Article

Publication Date

6-1-2015

Abstract

Background and Purpose—The blood-brain barrier (BBB) is a selectively permeable cerebrovascular endothelial barrier that maintains homeostasis between the periphery and central nervous system (CNS). 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 (LPS) challenge on infarct volume, BBB permeability, infiltrated neutrophils and functional outcomes following murine transient middle cerebral artery occlusion (tMCAO) in vivo; mitochondrial evaluation of cerebrovascular endothelial cells (CVECs) challenged by LPS 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 following tMCAO. Results—We report here that LPS worsens ischemic stroke outcome and increases BBB permeability following tMCAO in mice. Further, we elucidate a novel mechanism that compromised mitochondrial function accounts for increased BBB permeability as evidenced by: LPS-induced reductions in oxidative phosphorylation and subunit expression of respiratory chain complexes in CVECs, a compromised BBB permeability induced by pharmacological inhibition of mitochondrial function in CVECs in vitro and in an in vivo animal model, and worsened stroke outcomes in tMCAO mice following 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.

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