Phosphorylation of caveolin-1 regulates oxidant-induced pulmonary vascular permeability via paracellular and transcellular pathways.

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 (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.