Phosphorylation of caveolin-1 regulates oxidant-induced pulmonary vascular permeability via paracellular and transcellular pathways.
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.
Sun
Yu
Y
Department of Pharmacology (m/c 868), University of Illinois at Chicago, Chicago, IL 60612, USA.
Hu
Guochang
G
Zhang
Xiumei
X
Minshall
Richard D
RD
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
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