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ADAM15‐mediated glycocalyx injury contributes to vascular barrier dysfunction during inflammation
Author(s) -
Yang Xiaoyuan,
Meegan Jamie E.,
Jannaway Melanie,
Yuan Sarah Y.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.834.1
Subject(s) - glycocalyx , microbiology and biotechnology , inflammation , lipopolysaccharide , chemistry , endothelium , biology , immunology , endocrinology
Endothelial surface glycocalyx composed of glycosaminoglycans, proteoglycans and glycoproteins plays an important role in regulating vascular barrier integrity. A disintegrin metalloprotease 15 (ADAM15) is a membrane‐associated sheddase which has recently been characterized as a mediator of endothelial hyperpermeability during inflammation. This study tested the hypothesis that ADAM15 contributes to microvascular barrier dysfunction by damaging glycocalyx integrity. Intravital microscopic analysis of mouse mesenteric microcirculation showed a significant reduction in the thickness of glycocalyx layer on the endothelial surface following bacterial lipopolysaccharide (LPS) injection; this response was greatly attenuated in ADAM15 −/− mice. In parallel, LPS treatment caused a higher normalized plasma level of low molecular weight hyaluronan, an important component of glycocalyx that can be degraded into small fragments, in wild type mice compared to ADAM15 −/− mice. Functionally, inflammation‐induced plasma leakage in mesenteric microvessels was ameliorated in the absence of ADAM15. Further molecular and confocal imaging analyses of cultured endothelial cells revealed evidence of ADAM15 co‐localization with CD44, a transmembrane glycoprotein that binds hyaluronan and stabilizes its attachment to cell surface. LPS stimulation resulted in an increase in ADAM15 expression and a decrease in CD44 and hyaluronan expression on endothelial cell surface, an effect greatly inhibited during siRNA knockdown of ADAM15. Moreover, the LPS‐induced increase in CD44 release into conditioned media was attenuated during ADAM15 knockdown. Taken together, the data suggest the involvement of ADAM15 in glycocalyx injury and endothelial barrier leakage during inflammation.