Endothelial NLRP3 pyroptotic as a trigger for blood brain barrier disruption and neurotoxic Astrogenesis in chronic...

Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea, leads to cognitive deficits, yet the cellular mechanisms between CIH and neural injury remain poorly defined. This study identifies endothelial pyroptosis as a trigger in CIH-induced neurovascular dysfunction. Using a combination of in vivo CIH animal modeling, primary astrocyte culture, endothelial cell line, molecular profiling, and behavioral experiments, we demonstrate that CIH specifically activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in brain microvascular endothelial cells, culminating in Gasdermin D-mediated pyroptosis and the release of mature interleukin‑1β and interleukin‑18. Conditioned medium from these pyroptotic endothelial cells directly induced primary astrocytes to adopt a neurotoxic A1 phenotype, characterized by upregulation of complement component 3. This A1 transformation, in turn, compromised endothelial barrier integrity, evidenced by reduced claudin-5 expression. Genetic knockdown of NLRP3 in endothelial cells or inhibition with MCC950 in vivo suppressed pyroptosis, blunted A1 astrocyte activation, preserved blood-brain barrier function, and rescued CIH-associated spatial memory impairments. Our findings establish endothelial NLRP3-dependent pyroptosis as a necessary upstream mechanism that drives astrocytic maladaptation, which in turn actively disrupts blood-brain barrier integrity, highlighting a pivotal target for mitigating cognitive decline in hypoxic disorders.