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

Summary

In aged mice, anesthesia and surgery selectively increased hippocampal blood-brain barrier permeability, accompanied by neuroinflammation and cognitive decline. Endothelial-specific Piezo1 deletion or brain endothelial Nox4 knockdown restored barrier integrity and improved cognition, whereas the Piezo1 agonist Yoda1 worsened barrier disruption, identifying a potentially targetable Piezo1-Nox4 axis.

Key Findings

• Anesthesia and surgery increased blood-brain barrier permeability specifically in the hippocampus of aged mice.
• Endothelial-specific Piezo1 deletion improved hippocampal barrier integrity, reduced neuroinflammation, and ameliorated cognitive decline.
• Piezo1 activation induced Nox4, while AAV-BR1-mediated endothelial Nox4 knockdown blocked barrier breakdown and neuroinflammation.

Clinical Implications

The Piezo1-Nox4 pathway could eventually support preventive or therapeutic strategies for postoperative neurocognitive disorders in older adults. No current clinical recommendation can be made because the evidence is limited to aged mice and human safety, dosing, and target engagement are unknown.

Limitations

• The findings were generated in aged mice and may not reproduce the heterogeneous causes of postoperative cognitive decline in humans.
• The study does not establish the safety, pharmacokinetics, therapeutic window, or feasibility of Piezo1-Nox4 inhibition in patients.

Future Directions

Research should validate hippocampal endothelial Piezo1-Nox4 activation in human perioperative samples and determine whether it identifies patients at high risk for postoperative neurocognitive disorders. Selective inhibitors, delivery systems, and clinically relevant timing should be evaluated first in translational models and then in carefully monitored clinical trials.