title: Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities.
abstract: Loss of lung-fluid homeostasis is the hallmark of acute lung injury (ALI). Association of catenins and actin cytoskeleton with vascular endothelial (VE)-cadherin is generally considered the main mechanism for stabilizing adherens junctions (AJs), thereby preventing disruption of lung vascular barrier function. The present study identifies endothelial focal adhesion kinase (FAK), a nonreceptor tyrosine kinase that canonically regulates focal adhesion turnover, as a novel AJ-stabilizing mechanism. In wild-type mice, induction of ALI by intraperitoneal administration of lipopolysaccharide or cecal ligation and puncture markedly decreased FAK expression in lungs. Using a mouse model in which FAK was conditionally deleted only in endothelial cells (ECs), we show that loss of EC-FAK mimicked key features of ALI (diffuse lung hemorrhage, increased transvascular albumin influx, edema, and neutrophil accumulation in the lung). EC-FAK deletion disrupted AJs due to impairment of the fine balance between the activities of RhoA and Rac1 GTPases. Deletion of EC-FAK facilitated RhoA's interaction with p115-RhoA guanine exchange factor, leading to activation of RhoA. Activated RhoA antagonized Rac1 activity, destabilizing AJs. Inhibition of Rho kinase, a downstream effector of RhoA, reinstated normal endothelial barrier function in FAK-/- ECs and lung vascular integrity in EC-FAK-/- mice. Our findings demonstrate that EC-FAK plays an essential role in maintaining AJs and thereby lung vascular barrier function by establishing the normal balance between RhoA and Rac1 activities.
authors.affiliation: Dept. of Pharmacology, The Univ. of Illinois, College of Medicine, 835 S. Wolcott Ave., Chicago, IL 60612. dmehta@uic.edu.
authors.forename: Tracy Thennes
authors.initials: TT
authors.lastname: Schmidt
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tauseef
authors.forename: Lili
authors.initials: L
authors.lastname: Yue
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
authors.forename: Joachim
authors.initials: J
authors.lastname: Gothert
authors.forename: Tang-Long
authors.initials: TL
authors.lastname: Shen
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
authors.forename: Sanda
authors.initials: S
authors.lastname: Predescu
authors.forename: Ruxana
authors.initials: R
authors.lastname: Sadikot
authors.forename: Dolly
authors.initials: D
authors.lastname: Mehta
mesh_terms: D000818:Animals; D001826:Body Fluids / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D004727:Endothelium / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004795:Enzyme Stability; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D055370:Lung Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000378:metabolism*; D009928:Organ Specificity; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; D051416:Focal Adhesion Protein-Tyrosine Kinases; C045073:Cre recombinase; D019426:Integrases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
keywords: acute lung injury; adherens junctions; endothelial barrier; focal adhesion kinase