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 ¹²⁵I-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.