Inhibiting the Endothelial Mechanosensitive Channel Piezo1 Restores Hippocampal Blood–Brain Barrier Integrity to Improve Anesthesia‐ and Surgery‐Induced Cognitive Decline

ABSTRACT Approximately 10%–30% of elderly patients experience cognitive decline after general anesthesia and surgery. However, how specific brain regions coordinate cellular and molecular networks to mediate cognitive decline remains unknown. Here, we revealed that the hippocampus, but not other cognitive‐related brain regions, exhibits increased blood–brain barrier (BBB) permeability, leading to neuroinflammation activation and cognitive decline after general anesthesia and surgery in aged mice. Mechanistically, anesthesia and surgery induce expression of the mechanosensitive channel Piezo1 in hippocampal endothelial cells (ECs) of aged mice. Inducible EC‐specific deletion of Piezo1 restores hippocampal BBB integrity, inhibits neuroinflammation activation, and improves cognitive decline in aged mice following anesthesia and surgery. Conversely, injection of the Piezo1 agonist Yoda1 promotes hippocampal BBB breakdown. Moreover, activation of Piezo1 induces Nox4, which mediates hippocampal BBB breakdown and neuroinflammation activation after anesthesia and surgery in aged mice. Therapeutically, AAV‐BR1 transduction to brain microvascular ECs for the knockdown of endothelial Nox4 blocks Piezo1‐mediated hippocampal BBB breakdown and neuroinflammation activation. Overall, inhibiting the endothelial Piezo1‐Nox4 axis restores hippocampal BBB integrity to improve anesthesia‐ and surgery‐induced cognitive decline in aged mice, highlighting potential therapeutic strategies.