ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function

Dan Cui, Mitsuru Arima, Keiyo Takubo, Tokuhiro Kimura, Keisuke Horiuchi, Takuya Minagawa, Satoshi Matsuda, Eiji Ikeda

Research output: Contribution to journalArticle

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Abstract

Neural vascular barrier is essential for the life of multicellular organisms, and its impairment by tissue hypoxia is known to be a central of pathophysiology accelerating the progression of various intractable neural diseases. Therefore, the molecules involved in hypoxia-induced impairment of vascular barrier can be the targets to establish new therapies for intractable diseases. Here, we demonstrate that a disintegrin and metalloproteinases (ADAMs) 12 and 17 expressed in endothelial cells are the molecules responsible for the impairment of neural vascular barrier by hypoxia. Brain microvascular endothelial cells in vitro lost their barrier properties immediately after hypoxic stimulation through diminished localization of claudin-5, a tight junction molecule, on cell membranes. Hypoxic disappearance of claudin-5 from cell membranes and the consequent loss of barrier properties were completely suppressed by inhibition of the metalloproteinase activity which was found to be attributed to ADAM12 and ADAM17. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the in vivo neural vasculature under hypoxia from the loss of barrier function. This is the first report to specify the molecules which are responsible for hypoxia-induced impairment of neural vascular barrier and furthermore can be the targets of new therapeutic strategies for intractable neural diseases.

Original languageEnglish
Article number12796
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 2015 Aug 5

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Blood Vessels
Claudin-5
Metalloproteases
Endothelial Cells
Cell Membrane
Disintegrins
Tight Junctions
ADAM17 Protein
Hypoxia
Brain
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Cui, D., Arima, M., Takubo, K., Kimura, T., Horiuchi, K., Minagawa, T., ... Ikeda, E. (2015). ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function. Scientific Reports, 5, [12796]. https://doi.org/10.1038/srep12796

ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function. / Cui, Dan; Arima, Mitsuru; Takubo, Keiyo; Kimura, Tokuhiro; Horiuchi, Keisuke; Minagawa, Takuya; Matsuda, Satoshi; Ikeda, Eiji.

In: Scientific Reports, Vol. 5, 12796, 05.08.2015.

Research output: Contribution to journalArticle

Cui, D, Arima, M, Takubo, K, Kimura, T, Horiuchi, K, Minagawa, T, Matsuda, S & Ikeda, E 2015, 'ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function', Scientific Reports, vol. 5, 12796. https://doi.org/10.1038/srep12796
Cui, Dan ; Arima, Mitsuru ; Takubo, Keiyo ; Kimura, Tokuhiro ; Horiuchi, Keisuke ; Minagawa, Takuya ; Matsuda, Satoshi ; Ikeda, Eiji. / ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function. In: Scientific Reports. 2015 ; Vol. 5.
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