title: Phosphorylation of caveolin-1 regulates oxidant-induced pulmonary vascular permeability via paracellular and transcellular pathways.
abstract: BACKGROUND
  Oxidants are important signaling molecules known to increase endothelial permeability, although the mechanisms underlying permeability regulation are not clear.
  
  
  OBJECTIVE
  To define the role of caveolin-1 in the mechanism of oxidant-induced pulmonary vascular hyperpermeability and edema formation.
  
  
  RESULTS
  Using genetic approaches, we show that phosphorylation of caveolin-1 Tyr14 is required for increased pulmonary microvessel permeability induced by hydrogen peroxide (H(2)O(2)). Caveolin-1-deficient mice (cav-1(-/-)) were resistant to H(2)O(2)-induced pulmonary vascular albumin hyperpermeability and edema formation. Furthermore, the vascular hyperpermeability response to H(2)O(2) was completely rescued by expression of caveolin-1 in cav-1(-/-) mouse lung microvessels but was not restored by the phosphorylation-defective caveolin-1 mutant. The increase in caveolin-1 phosphorylation induced by H(2)O(2) was dose-dependently coupled to both increased (125)I-albumin transcytosis and decreased transendothelial electric resistance in pulmonary endothelial cells. Phosphorylation of caveolin-1 following H(2)O(2) exposure resulted in the dissociation of vascular endothelial cadherin/beta-catenin complexes and resultant endothelial barrier disruption.
  
  
  CONCLUSIONS
  Caveolin-1 phosphorylation-dependent signaling plays a crucial role in oxidative stress-induced pulmonary vascular hyperpermeability via transcellular and paracellular pathways. Thus, caveolin-1 phosphorylation may be an important therapeutic target for limiting oxidant-mediated vascular hyperpermeability, protein-rich edema formation, and acute lung injury.
authors.affiliation: Department of Pharmacology (m/c 868), University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Guochang
authors.initials: G
authors.lastname: Hu
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007365:Intercellular Junctions / Q000378:metabolism; D008168:Lung / Q000098:blood supply*; D051379:Mice; D018345:Mice, Knockout; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011654:Pulmonary Edema / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014443:Tyrosine; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000418:Albumins; D015703:Antigens, CD; D015820:Cadherins; D051242:Caveolin 1; D006861:Hydrogen Peroxide; D016877:Oxidants; D016315:Proto-Oncogene Proteins c-abl; D014443:Tyrosine; D051176:beta Catenin; D019061:src-Family Kinases; D000099152:Cadherin 5; C495541:Cav1 protein, mouse; C495537:Cav1 protein, rat; C495268:Ctnnb1 protein, rat