Tyrosine phosphorylation of vascular endothelial cadherin and the regulation of microvascular permeability

Fiemu E. Nwariaku, Zijuan Liu, Xudong Zhu, Richard H. Turnage, George A. Sarosi, Lance S. Terada

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Background. Adherens junctions (AJ), by their association with the endothelial cytoskleton, maintain microvascular barrier integrity. Phosphorylation states of AJ proteins, such as vascular endothelial (VE) cadherin, can potentially alter the interactions between component AJ proteins. Furthermore, AJ protein phosphorylation is susceptible to regulation by inflammatory mediators. We previously demonstrated the importance of VE cadherin in tumor necrosis factor (TNF)-mediated endothelial permeability. We now postulate that TNF-induced endothelial permeability is associated with tyrosine phosphorylation of VE cadherin. Methods. Confluent monolayers of human umbilical vein endothelial cells were exposed to saline solution, TNF-α (100 U/mL) or TNF and the Src-tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. Permeability was assessed by fluorescein isothiocyanate-dextran flux. VE-cadherin phosphorylation was determined by immunoprecipitation and immunoblotting with antiphosphotyrosine antibody. Data are expressed as mean ± SEM and analyzed by analysis of variance. Results. TNF-α-induced tyrosine phosphorylation of VE cadherin and increased intercellular gap formation. These changes were associated with increased endothdial-cell monolayer permeability, all of which were prevented by 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. Exposure to an inactive tyrphostin, AG9 (negative control), did not prevent TNF-induced endothelial permeability. Conclusions. We conclude that tyrosine phosphorylation of VE cadherin is an important regulatory pathway associated with TNF-induced endothelial barrier dysfunction. Modulating AJ protein phosphorylation may provide targets for therapy during inflammation.

Original languageEnglish (US)
Pages (from-to)180-185
Number of pages6
JournalSurgery
Volume132
Issue number2
DOIs
StatePublished - Aug 2002

ASJC Scopus subject areas

  • Surgery

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