Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities

Am J Physiol Lung Cell Mol Physiol. 2013 Aug 15;305(4):L291-300. doi: 10.1152/ajplung.00094.2013. Epub 2013 Jun 14.


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.

Keywords: acute lung injury; adherens junctions; endothelial barrier; focal adhesion kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Fluids / metabolism
  • Endothelial Cells / enzymology
  • Endothelial Cells / pathology
  • Endothelium / enzymology*
  • Endothelium / pathology
  • Endothelium / physiopathology
  • Enzyme Stability
  • Focal Adhesion Protein-Tyrosine Kinases / deficiency
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Gene Deletion*
  • Humans
  • Integrases / metabolism
  • Lung / blood supply*
  • Lung / enzymology
  • Lung / pathology
  • Lung / physiopathology*
  • Lung Injury / enzymology
  • Lung Injury / pathology
  • Lung Injury / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuropeptides / metabolism*
  • Organ Specificity
  • rac1 GTP-Binding Protein / metabolism*
  • rhoA GTP-Binding Protein / metabolism*


  • Neuropeptides
  • Rac1 protein, mouse
  • Focal Adhesion Protein-Tyrosine Kinases
  • Cre recombinase
  • Integrases
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein