Journal
STROKE
Volume 51, Issue 2, Pages 619-627Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.119.027531
Keywords
blood-brain barrier; E-selectin; ischemia; mice; vascular cell adhesion molecule-1
Categories
Funding
- National Key Research and Development Program of China [2016YFC1300600]
- Scientific Research and Innovation Program of Shanghai Education Commission [2019-01-07-00-02-E00064]
- National Natural Science Foundation of China [81771251, 81771244, 81801170, 81870921]
- K.C. Wong Education Foundation
- Science and Technology Commission of Shanghai Municipality [17ZR1413600]
- Science and Technology Opening Program of the Education Ministry of Henan Province [182106000061]
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Background and Purpose-Blood-brain barrier (BBB) disruption is a critical pathological feature after stroke. MicroRNA-126 (miR-126) maintains BBB integrity by regulating endothelial cell function during development. However, the role of miR-126-3p and -5p in BBB integrity after stroke is unclear. Here, we investigated whether miR-126-3p and -5p overexpression regulates BBB integrity after cerebral ischemia. Methods-alpha lentivirus carrying genes encoding miR-126-3p or -5p was stereotactically injected into adult male Institute of Cancer Research mouse brains (n=36). Permanent middle cerebral artery occlusion was performed 2 weeks after virus injection. Brain infarct volume, edema volume, and modified neurological severity score were assessed at 1 and 3 days after ischemia. Immunostaining of ZO-1 (zonula occludens-1) and occludin was used to evaluate BBB integrity. IL-1 beta (interleukin-1 beta), TNF-alpha (tumor necrosis factor-alpha), VCAM-1 (vascular cell adhesion molecule-1), and E-selectin expression levels were determined by real-time polymerase chain reaction and Western blot analysis. Results-The expression of miR-126-3p and -5p decreased at 1 and 3 days after ischemia (P<0.05). Injection of lentiviral miR-126-3p or -5p reduced brain infarct volume and edema volume (P<0.05) and attenuated the decrease in ZO-1/occludin protein levels and IgG leakage at 3 days after stroke (P<0.05). Injection of lentiviral miR-126-5p improved behavioral outcomes at 3 days after stroke (P<0.05). miR-126-3p and -5p overexpression downregulated the expression of proinflammatory cytokines IL-1 beta and TNF-alpha and adhesion molecules VCAM-1 and E-selectin, as well as decreased MPO+ (myeloperoxidase positive) cell numbers at 3 days after ischemia (P<0.05). Conclusions-miR-126-3p and -5p overexpression reduced the expression of proinflammatory cytokines and adhesion molecules, and attenuated BBB disruption after ischemic stroke, suggesting that miR-126-3p and -5p are new therapeutic targets in the acute stage of stroke. Visual Overview-An online visual overview is available for this article.
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