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.
Highlights
Barrier in various pathological situations of neural tissues, and hypoxia-induced impairment of vascular barrier function works as a core pathological factor to accelerate the progression of intractable neural diseases including diabetic retinopathy and ischemic cerebral attack[1,6,7]
We have elucidated an aspect of regulatory mechanisms of neural vascular barrier by demonstrating for the first time that ADAM12 and ADAM17 in endothelial cells are the essential molecules for hypoxia-induced impairment of vascular barrier function
ADAM12 was originally identified as a transmembrane molecule involved in the fusion of muscle cells, and initially named meltrin α 18,19
Summary
Barrier in various pathological situations of neural tissues, and hypoxia-induced impairment of vascular barrier function works as a core pathological factor to accelerate the progression of intractable neural diseases including diabetic retinopathy and ischemic cerebral attack[1,6,7]. In order to specify the molecules which play the essential role in the impairment of neural vascular barrier by hypoxia, we have focused our study on the mechanisms of hypoxia-triggered changes in claudin-5 expression. Several molecules such as caveolin-1, caspases, matrix metalloproteinases (MMPs), ADAMs as well as molecules in ubiquitin-proteasomal system are reported to be involved in the processing of TJ molecules, the mechanisms of oxygen concentration-dependent regulation of claudin-5 expression remain unknown[10,11,12,13,14]
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