Downregulation of Nrp1 transcription promotes blood-brain barrier disruption following experimental cerebral ischemia-reperfusion

Disruption of the blood-brain barrier (BBB) following cerebral ischemia-reperfusion injury (CIRI) is a major factor in the pathophysiology of stroke. Endothelial cell-cell communication is essential for maintaining BBB integrity. By analyzing GSE227651 data, we found that a decrease in endothelial cell-cell communication mediated by Sema3/Nrp1 may be due to the downregulation of Nrp1 transcription, which could contribute to BBB breakdown after CIRI. We confirmed this hypothesis by using western blot analysis to show a reduction in Nrp1 protein levels in penumbra endothelial cells after CIRI in mice. We then overexpressed Nrp1 specifically in brain endothelial cells using adeno-associated virus in mice. Furthermore, Nrp1 overexpression had a protective effect on BBB integrity, as evidenced by a decrease in IgG and albumin leakage caused by CIRI in mice. Finally, we found that Nrp1 overexpression also reduced brain cell death and neurological deficits induced by cerebral ischemia-reperfusion in mice. Our findings suggest that Nrp1 downregulation may be a key factor in the breakdown of endothelial cell-cell communication and subsequent BBB disruption following CIRI. Targeting Nrp1-mediated pathways may be a promising approach for mitigating BBB damage and alleviating neurological consequences in stroke patients.