NADPH oxidase mediates vascular endothelial cadherin phosphorylation and endothelial dysfunction

Fiemu E. Nwariaku, Zijuan Liu, Xudong Zhu, Dorit Nahari, Christine Ingle, Feng Wu Ru, Ying Gu, George Sarosi, Lance S. Terada

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Vascular endothelial activation is an early step during leukocyte/endothelial adhesion and transendothelial leukocyte migration in inflammatory states. Leukocyte transmigration occurs through intercellular gaps between endothelial cells. Vascular endothelial cadherin (VE-cadherin) is a predominant component of endothelial adherens junctions that regulates intercellular gap formation. We found that tumor necrosis factor (TNF) caused tyrosine phosphorylation of VE-cadherin, separation of lateral cell-cell junctions, and intercellular gap formation in human umbilical vein endothelial cell (HUVEC) monolayers. These events appear to be regulated by intracellular oxidant production through endothelial NAD(P)H (nicotinamide adenine dinucleotide phosphate) oxidase because antioxidants and expression of a transdominant inhibitor of the NADPH oxidase, p67(V204A), effectively blocked the effects of TNF on all 3 parameters of junctional integrity. Antioxidants and p67(V204A) also decreased TNF-induced JNK activation. Dominant-negative JNK abrogated VE-cadherin phosphorylation and junctional separation, suggesting a downstream role for JNK. Finally, adenoviral delivery of the kinase dead PAK1(K298A) decreased TNF-induced JNK activation, VE-cadherin phosphorylation, and lateral junctional separation, consistent with the proposed involvement of PAK1 upstream of the NADPH oxidase. Thus, PAK-1 acts in concert with oxidase during TNF-induced oxidant production and loss of endothelial cell junctional integrity.

Original languageEnglish (US)
Pages (from-to)3214-3220
Number of pages7
JournalBlood
Volume104
Issue number10
DOIs
StatePublished - Nov 15 2004

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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