Phosphorylation of Caveolin-1 Regulates Oxidant–Induced Pulmonary Vascular Permeability via Paracellular and Transcellular Pathways

• Published in: Circulation research 2009-09, Vol.105 (7), p.676-685
• Main Authors: Sun, Yu, Hu, Guochang, Zhang, Xiumei, Minshall, Richard D
• Format: Article
• Language: English
• Subjects: Albumins - metabolism; Animals; Antigens, CD - metabolism; beta Catenin - metabolism; Biological and medical sciences; Cadherins - metabolism; Capillary Permeability - drug effects; Caveolin 1 - deficiency; Caveolin 1 - genetics; Caveolin 1 - metabolism; Cells, Cultured; Dose-Response Relationship, Drug; Endocytosis; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Fundamental and applied biological sciences. Psychology; Hydrogen Peroxide - toxicity; Intercellular Junctions - metabolism; Lung - blood supply; Mice; Mice, Knockout; Microvessels - drug effects; Microvessels - metabolism; Oxidants - toxicity; Oxidative Stress - drug effects; Phosphorylation; Proto-Oncogene Proteins c-abl - metabolism; Pulmonary Edema - metabolism; Pulmonary Edema - prevention & control; Rats; Signal Transduction - drug effects; src-Family Kinases - metabolism; Time Factors; Tyrosine; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.201673

RATIONALE: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. METHODS AND RESULTS:Using genetic approaches, we show that phosphorylation of caveolin-1 Tyr14 is required for increased pulmonary microvessel permeability induced by hydrogen peroxide (H2O2). Caveolin-1–deficient mice (cav-1) were resistant to H2O2-induced pulmonary vascular albumin hyperpermeability and edema formation. Furthermore, the vascular hyperpermeability response to H2O2 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 H2O2 was dose-dependently coupled to both increased I-albumin transcytosis and decreased transendothelial electric resistance in pulmonary endothelial cells. Phosphorylation of caveolin-1 following H2O2 exposure resulted in the dissociation of vascular endothelial cadherin/β-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.