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(Circulation Research. 2009;105:676.)
© 2009 American Heart Association, Inc.

Cellular Biology

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

Yu Sun, Guochang Hu, Xiumei Zhang, Richard D. Minshall

From the Departments of Pharmacology (Y.S., G.H., R.D.M.) and Anesthesiology (G.H., R.D.M.) and Center for Lung and Vascular Biology (R.D.M.), University of Illinois at Chicago; and Institute of Pharmacology (Y.S., X.Z.), Shandong University School of Medicine, Jinan, Shandong, China.

Correspondence to Guochang Hu, MD, PhD, Department of Pharmacology (m/c 868), University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612. E-mail gchu{at}uic.edu

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.

Key Words: vascular endothelial barrier • transcytosis • adherens junctions • caveolin-1 • lung edema