Piezo1 disrupts blood-brain barrier via CaMKII/Nrf2 in ischemic stroke

Ischemic stroke (IS) leads to the disruption of blood-brain barrier (BBB) integrity, resulting in brain edema. In this process, endothelial cells, as a crucial component of the BBB, are subjected to external pressure and tensile stress. Piezo1, a mechanically-sensitive ion channel, may be activated by sensing these stresses, further exacerbating the destruction of the BBB. Our findings indicated that after cerebral ischemia/reperfusion (I/R) injury, the expression of Piezo1 in endothelial cells increased. In endothelial-specific Piezo1 knockout (Piezo1^ECKO) mice, brain damage, neurological deficits, and BBB disruption caused by I/R injury were significantly alleviated. Moreover, oxidative stress and the inflammatory response in the cerebral cortex induced by I/R were also reduced. In vitro, by activating or knocking out Piezo1 in bEnd.3 cells under oxygen-glucose deprivation/reperfusion (OGD/R), we observed similar effects, further corroborating the in vivo findings. To elucidate the molecular mechanism, we found that the protective effect of Piezo1 deficiency on BBB integrity is mediated by the alleviation of p-CaMKII and the enhancement of Nrf2 nuclear translocation. This, in turn, leads to the upregulation of NQO-1 and HO-1 expression. In summary, our research indicates that Piezo1 exacerbates BBB disruption after cerebral I/R injury by promoting oxidative stress, inflammation, and mitochondrial dysfunction. This process is closely linked to the activation of the Ca²⁺/CaMKII and Nrf2 pathways, suggesting that Piezo1 may be a potential therapeutic target for IS.