Pathological changes in the brain endothelium play an important role in the progression of ischemic stroke and the compromised BBB under ischemic stroke conditions cause neuronal damage. However, the pathophysiological mechanisms of the BBB under normal conditions and under ischemic stroke conditions have not been fully elucidated. The present study demonstrated that knockdown of TAR DNA-binding protein 43 (TDP-43) or overexpression of TDP43-CTFs35 inhibited tight junction protein expression, and mammalian sterile-20-like 1/2 (MST1/2) and YES-associated protein (YAP) phosphorylation in brain ECs and suppressed brain EC migration in vitro. The cytoplasmic TDP43-CTFs35 level was increased in brain ECs 24 h and 72 h after MCAO, but it disappeared 1 week after cerebral ischemia. The expression of tight junction proteins was also significantly deceased 24 h after MCAO and then gradually recovered at 72 h and 1 week after MCAO. The level of YAP phosphorylation was first significantly decreased 24 h after MCAO and then increased 72 h and 1 week after MCAO, accompanied by nuclear YAP translocation. The underlying mechanism is TDP43-CTFs35-mediated inhibition of Hippo signaling pathway activity through the dephosphorylation of MST1/2, which leads to the inhibition of YAP phosphorylation and the subsequent impairment of brain EC migration and tight junction protein expression. This study provides new insights into the mechanisms of brain vascular EC regulation, which may impact on BBB integrity after cerebral ischemic injury.
Keywords: BBB; Endothelial cell; Hippo signaling pathway; MCAO; TDP43; TDP43-CTFs35.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.