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

It has been reported that more than 300 million surgeries and anesthesia procedures are performed annually worldwide, with the majority involving general anesthesia. This number is increasing with the aging of the global population [, , ]. Patients may suffer from abnormalities in cognition, consciousness, and emotions, including short‐term delirium and cognitive impairment, which may also contribute to a higher risk of long‐term cognitive decline and even dementia after anesthesia and surgery. Approximately 10%–30% of elderly patients experience cognitive decline after general anesthesia and surgery [, ]. In addition, the incidence of dementia is significantly higher in elderly orthopedic patients receiving inhalation anesthesia versus regional anesthesia, implicating general anesthesia/surgery in cognitive impairment. Postoperative cognitive decline increases medical expenses and impairs patient recovery and quality of life [, , , , ]. The pathogenesis of postoperative cognitive decline remains controversial, involving peripheral inflammation, neuroinflammation, oxidative stress, and microbial imbalance, with growing recognition of blood–brain barrier (BBB) dysfunction. The BBB, a structural and functional barrier comprising endothelial cells (ECs), pericytes, astrocyte endfeet, and tight junctions (TJs), restricts inflammatory factors and immune cells from entering the brain, and its disruption may intensify neuroinflammation and disturb cerebral homeostasis [, , ]. Indeed, BBB dysfunction, measured by magnetic resonance imaging (MRI) and cerebrospinal fluid‐to‐plasma albumin ratio (CPAR), after anesthesia and surgery is a typical clinical phenomenon and may be associated with postoperative cognitive decline [, , ]. However, the underlying pathophysiological process and specific molecular mechanisms remain unclear. ECs are key to the structural function and integrity of the BBB. Brain endothelial cells (BECs) can regulate the balance of the brain environment through carrier‐mediated transport, receptor‐mediated transport, active efflux, and ion transport. BECs may also mediate paracrine effects to maintain brain homeostasis and remove metabolic waste. To ensure brain energy metabolism, glucose transporters, which are prominently expressed on BECs, transport glucose from the blood to the brain. BECs also play an important role in the immune response [, , , ]. Abnormal BEC function can lead to BBB dysfunction, neuroinflammation, and even cognitive impairment. Wei et al. used lipopolysaccharide (LPS) to construct a mouse model of sepsis and found that LPS can activate the caspase‐4/11‐GSDMD signaling pathway in BECs, resulting in inflammatory destruction of the BBB []. The physical barrier depends on the TJs (e.g., claudin‐5). Claudin‐5 overexpression can improve stress‐related BBB dysfunction and delirium in mice and inhibit proinflammatory factors []. Zong et al. found that EC TRPM2 regulates oxidative stress and calcium overload, thereby affecting EC function and BBB permeability in the context of ischemic stroke []. In addition, previous studies have shown that anesthesia and surgery may lead to dysfunction in the BBB microstructure and decrease TJs, predominantly released by BECs, further suggesting a link between BEC dysfunction and BBB breakdown after anesthesia and surgery [, , ]. Collectively, BECs dysfunction impairs BBB integrity and is closely associated with neuroinflammation and cognitive decline. However, how specific brain regions coordinate cellular and molecular networks to mediate cognitive decline remains unknown. Piezo1 is a mechanosensitive ion channel activated by shear stress and membrane tension that triggers calcium influx and downstream signaling []. Mechanical sensing in the brain is essential for homeostasis []. During anesthesia/surgery, BECs encounter cerebral blood flow fluctuations [, ] and increased leukocyte infiltration []. The mechanical forces generated during leukocyte transendothelial migration, in synergy with fluid shear stress, increase membrane tension and impair ECs barrier function []. These findings implicate BECs mechanosensing in perioperative BBB disruption.