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Background: Growing evidence suggests that Vitamin D hormone deficiency (VDHdef) is a risk factor for ischemic stroke and its severity. Blood-brain barrier (BBB) impairment is a marker of secondary cerebral injury following stroke and is associated with an increased propensity for hemorrhage. Our in vitro work showed that VDH treatment reduces BBB damage after hypoxia/reperfusion injury via VDR-mediated NF-kB-MMP9 pathways. We explored the role of VDH in maintaining BBB integrity in a rodent model of stroke.Methods: Male Wistar rats (n=48) were assigned to one of two diet cohorts, VDH-sufficient (VDHsuf) and VDHdef. The VDHsuf group was fed standard chow and the VDHdef group was fed a VDH-null version of the same diet for 8 weeks. Animals from both cohorts received either sham or transient middle cerebral artery occlusion (tMCAO) surgeries and were assigned to one of 4 groups (n=12/group): sham VDHsuf, MCAO+VDHsuf, Sham+VDHdef, or MCAO+VDHdef. Rats were killed at 72h and one group of animals (n=6) was used for immunohistological assays and other group (n=6) used for western blot assays. Their brains were evaluated for BBB permeability, MMP-9 activity, alteration of TJ proteins and VDR expression.Results: VDHdef induced a significant increase in BBB permeability as measured by IgG extravasation in sham VDHdef control rats. Following MCAO, expression of MMP-9 and the TJ proteins occludin and claudin-5 increased significantly in the MCAO+VDHdef group compared to the MCAO+VDHsuf group. IgG extravasation after MCAO was observed to be significantly higher in the MCAO+VDHdef than the MCAO+VDHsuf group, indicating more severe BBB injury in the VDHdef group.Conclusion: Our result showed greater BBB dysfunction in the sham and MCAO groups in the VDHdef diet than in the control cohort, indicating more severe BBB injury in rats fed a VDHdef diet. This finding that VDH status modulates BBB integrity may help explain the clinical correlations between low serum VDH levels and stroke.