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.

Basigin can be a therapeutic target to restore the retinal vascular barrier function in the mouse model of diabetic retinopathy

“…1a). Results of a confocal imaging study with quantitative analysis8 (Fig. 1b,c) as well as a Western blot analysis after biotinylation of cell membrane-localized molecules (Fig.…”

“…After washing with PBS, they were mounted in fluorescence mounting medium (Dako, Glostrup, Denmark), and observed under a Zeiss LSM5 Pascal laser confocal microscope (Carl Zeiss, Jena, Germany). A quantitative analysis of the fluorescent intensity of claudin-5 on cell membranes was performed according to the methods described in our previous report8. In brief, 3 fields were randomly photographed and 3 straight lines were drawn on each photograph.…”

“…Among the TJ molecules, claudin-5 is shown to be a key molecule which confers the barrier properties on neural vascular endothelial cells67. As for hypoxia-triggered impairment of neural vascular barrier, we have focused our study on the changes in claudin-5 expression and demonstrated that a disintegrin and metalloproteinases (ADAMs) 12 and 17 are essential molecules for neural vascular barrier impairment under hypoxia8. However, no molecules responsible for inflammation-triggered disruption of neural vascular barrier have been specified.…”

Sightings, edited by Erik R. Swenson and Peter Bärtsch

“…Hypoxia increases BBB permeability and this may in some individuals contribute to the development of AMS. To study the role of two metalloproteinases, ADAM (a disintegrin and metalloproteinase) 12 and 17 in hypoxia-mediated impairment of neural vascular barrier function, Cui et al (2015) exposed mouse brain microvascular endothelial cell monolayers to 1% oxygen. As a result, the monolayers became leaky and displayed a loss of claudin-5 localization at gap junctions.…”

Membrane-anchored proteases in endothelial cell biology

“…Several ADAMs mediate the shedding of cell-cell adhesion molecules to modulate vascular permeability during excessive inflammation and hypoxia [27,74]. Both ADAM12 and ADAM17 were recently reported to contribute to impaired neural vascular barrier function induced by hypoxia through the degradation of claudin-5 in brain microvascular endothelial cells [34**]. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the loss of barrier function in retinal neural vasculature in vivo under hypoxic conditions.…”