Zinc Overload in Microvessels Contributes to Blood-Brain Barrier Disruption by Activating the JAK2 Pathway After Cerebral Ischemia/Reperfusion

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.