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

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Abstract
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 transendothelia...

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