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Oxidants, generated by activated neutrophils, have been implicated in the pathophysiology of vascular disorders and lung injury; however, mechanisms of oxidant-mediated endothelial barrier dysfunction are unclear. Here, we have investigated the role of focal adhesion kinase (FAK) in regulating hydrogen peroxide (H2 O2 )-mediated tyrosine phosphorylation of intercellular adhesion proteins and barrier function in endothelium. Treatment of bovine pulmonary artery endothelial cells (BPAECs) with H2 O2 increased tyrosine phosphorylation of FAK, paxillin, β-catenin, and vascular endothelial (VE)-cadherin and decreased transendothelial electrical resistance (TER), an index of cell-cell adhesion and/or cell-matrix adhesion. To study the role of FAK in H2 O2 -induced TER changes, BPAECs were transfected with vector or FAK wild-type or FAK-related non-kinase (FRNK) plasmids. Overexpression of FRNK reduced FAK expression and attenuated H2 O2 -mediated tyrosine phosphorylation of FAK, paxillin, β-catenin, and VE-cadherin and cell-cell adhesion. Additionally, FRNK prevented H2 O2 -induced distribution of FAK, paxillin, β-catenin, or VE-cadherin toward focal adhesions and cell-cell adhesions but not actin stress fiber formation. These results suggest that activation of FAK by H2 O2 is an important event in oxidant-mediated VE barrier function regulated by cell-cell and cell-matrix contacts.
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