Research ArticleNeuroscience

Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke

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Science Signaling  07 Apr 2020:
Vol. 13, Issue 626, eaay5686
DOI: 10.1126/scisignal.aay5686

Breaking down barriers

Stroke decreases the function of the microvascular endothelial cells in the blood-brain barrier. The resulting immune cell infiltration and solute leak exacerbate the neuronal death caused by ischemic injury. Ma et al. found that endothelial cell–specific ablation of the miR-15a/16-1 microRNA cluster protected mice from ischemic brain damage. Analysis of cultured microvascular endothelial cells showed that the miR-15a/16-1 cluster targeted the gene encoding the tight junction protein claudin-5, which is critical for the barrier function of these cells. These results suggest that antagonizing this microRNA cluster may prevent the breakdown of the blood-brain barrier that occurs after stroke.

Abstract

The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.

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