ADAM15 regulates endothelial permeability and neutrophil migration via Src/ERK1/2 signalling

Chongxiu Sun, MacK H. Wu, Mingzhang Guo, Mark L. Day, Eugene S Lee, Sarah Y. Yuan

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

AimsEndothelial barrier dysfunction is a key event in the pathogenesis of vascular diseases associated with inflammation. ADAM (a disintegrin and metalloprotease) 15 has been shown to contribute to the development of vascular inflammation. However, its role in regulating endothelial barrier function is unknown. The aim of this study was to examine the effect of ADAM15 on endothelial permeability and its underlying mechanisms.Methods and resultsBy measuring albumin transendothelial flux and transendothelial electric resistance in cultured human umbilical vein endothelial cell monolayers, we found that depletion of ADAM15 expression via siRNA decreased endothelial permeability and attenuated thrombin-induced barrier dysfunction. In contrast, endothelial cells overexpressing either wild-type or catalytically dead mutant ADAM15 displayed a higher basal permeability and augmented hyperpermeability in response to thrombin. In addition, ADAM15 knockdown inhibited whereas ADAM15 overexpression promoted neutrophil transendothelial migration. Further molecular assays revealed that ADAM15 did not cleave vascular endothelial-cadherin or cause its degradation. However, overexpression of ADAM15 promoted extracellular signal-regulated kinase (ERK)1/2 phosphorylation in both non-stimulated and thrombin-stimulated endothelial cells in a protease activity-independent manner. Pharmacological inhibition of Src kinase or ERK activation reversed ADAM15-induced hyperpermeability and neutrophil transmigration.ConclusionThe data provide evidence for a novel function of ADAM15 in regulating endothelial barrier properties. The mechanisms of ADAM15-induced hyperpermeability involve Src/ERK1/2 signalling independent of junction molecule shedding.

Original languageEnglish (US)
Pages (from-to)348-355
Number of pages8
JournalCardiovascular Research
Volume87
Issue number2
DOIs
StatePublished - 2010

Keywords

  • Endothelial permeability
  • Metalloproteinase
  • Signal transduction
  • Vascular inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology
  • Medicine(all)

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