miR-21 alleviates secondary blood–brain barrier damage after traumatic brain injury in rats

• Elevation of miR-21 level in BMVECs is a protective response following TBI.
• Upregulation of miR-21 level in BMVECs can improve the neurological outcome of TBI.
• miR-21 alleviates TBI-associated BBB leakage.
• miR-21 reduces TBI-induced loss of tight junction proteins.
• miR-21 promotes the expression of Ang-1/Tie-2 axis in BMVECs after TBI.

Our recent studies have identified increased expression of miR-21 in brain following traumatic brain injury (TBI), which alleviated brain edema that related to the blood–brain barrier (BBB) leakage. To analyze the potential effect of miR-21 on secondary BBB damage after TBI, we employed the fluid percussion injury rat model and manipulated the expression level of miR-21 in brain. We found that miR-21 level in brain microvascular endothelial cells (BMVECs) in lesioned cerebral cortex can be upregulated or downregulated by intracerebroventricular infusion of miR-21 agomir or antagomir. Upregulated miR-21 level conferred a better neurological outcome of TBI, and alleviated TBI-induced secondary BBB damage and loss of tight junction proteins. To explore the molecular mechanism underlying this protective effect, we detected the impact of miR-21 on the expression of Angiopoietin-1(Ang-1) and Tie-2, which can promote the expression of tight junction proteins and amplify BBB stabilization. We found that miR-21 exerts the protective effect on BBB by activating the Ang-1/Tie-2 axis in BMVECs. Thus, miR-21 could be a potential therapeutic target for interventions of secondary BBB damage after TBI.