Journal
AGING-US
Volume 11, Issue 23, Pages 11391-11415Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.102537
Keywords
blood-brain barrier; pericytes; matrix metalloproteinase-9; nuclear factor kappa B; NOTCH3
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Funding
- National Natural Science Foundation of China [81671068, 81873727]
- Health Commission of Henan Province [201701020]
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The pathophysiological mechanism of white matter hyperintensities of cerebral small vessel disease (CSVD) includes an impaired blood-brain barrier (BBB) with increased permeability. Neuroinflammation likely contributes to the disruption of the BBB in CSVD. Therefore, understanding the molecular mechanism of how neuroinflammation causes BBB damage is essential to preventing BBB disruption in CSVD. Matrix metalloproteinase 9 (MMP-9) contributes to BBB damage in neuroinflammatory diseases. In this study, we observed that interleukin-1 beta (IL-1 beta)-induced MMP-9 secretion in pericytes increased BBB permeability to sodium fluorescein (Na-F) by damaging the disruption of VE-cadherin, occludin, claudin-5, and zonula occludin-1 (ZO-1). Melatonin reduced BBB permeability to Na-F and inhibited the disruption of the adherens and tight junction proteins. Melatonin also downregulated MMP-9 and upregulated tissue inhibitor of metalloproteinases 1 (TIMP-1) gene expression, which decreased the MMP-9/TIMP-1 ratio. In addition, nuclear translocation of NF-kappa B/p65 induced by IL-1 beta in pericytes upregulated MMP-9 expression, which was inhibited by the NF-kappa B inhibitor PDTC. However, the NOTCH3 inhibitor DAPT significantly inhibited NF-kappa B/p65 translocation to the nucleus, while melatonin in combination with DAPT significantly prevented NF-kappa B/p65 translocation than DAPT alone. Our results suggest that melatonin reduced MMP-9-induced permeability of the BBB. Melatonin reduced MMP-9 expression and activity, which was induced by IL-1 beta through the regulation of the NOTCH3/NF-kappa B signaling pathway in pericytes, suggesting that pericytes regulate BBB integrity and function.
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