ABSTRACT Aims Stroke is one of the leading causes of adult disability and death worldwide. Inflammation‐induced microvascular dysfunction and increased blood–brain barrier (BBB) permeability are major contributors to cerebral ischemia/reperfusion (I/R) injury. Previous studies have shown that zinc accumulation in microvessels contributes to BBB disruption following I/R. However, the mechanisms linking zinc accumulation to microvascular inflammation remain poorly understood. Methods We investigated whether the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) inflammatory pathway mediates microvascular zinc overload‐induced BBB damage, using the model of I/R rats, endothelial cells and neuron‐specific zinc transporter 3 knockout (ZnT3‐cKO) mice. Results Our findings in I/R rats and endothelial cells revealed that zinc accumulation in microvessels activated JAK2, promoting mitochondrial translocation of phosphorylated STAT3 (p‐STAT3) and exacerbating BBB disruption. These effects were significantly suppressed by zinc chelation. Furthermore, inhibition of neuronal zinc release in ZnT3‐cKO mice markedly reduced zinc accumulation and JAK2 activation in ischemic microvessels. ZnT3 knockout also prevented mitochondrial translocation of p‐STAT3, attenuated mitochondrial dysfunctions, and abolished zinc overload‐induced BBB permeability following I/R. Conclusion This study suggests that zinc accumulation in microvessels contributes to I/R‐induced BBB damage through JAK2/STAT3 signaling and highlights a potential therapeutic target for preserving vascular integrity after stroke.
Guo et al. (Wed,) studied this question.
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