title: ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function.
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.
authors.affiliation: Department of Pathology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Dan
authors.initials: D
authors.lastname: Cui
authors.affiliation: 1] Department of Pathology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan [2] Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka City, Fukuoka 812-8582, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Arima
authors.affiliation: 1] Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan [2] Departments of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.affiliation: Department of Pathology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
authors.affiliation: Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Minagawa
authors.affiliation: Department of Cell Signaling, Institute of Biomedical Sciences, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: Department of Pathology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ikeda
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000072199:ADAM12 Protein; D000072198:ADAM17 Protein; D000818:Animals; D001813:Blood-Retinal Barrier / Q000166:cytology / Q000201:enzymology; D015687:Cell Hypoxia; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D062507:Claudin-5 / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012160:Retina / Q000201:enzymology; D012171:Retinal Vessels / Q000166:cytology / Q000201:enzymology
chemical_list: D062507:Claudin-5; C491511:Cldn5 protein, mouse; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C096115:Adam12 protein, mouse; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse