Pulmonary Vascular Inflammation Promotes Caveolin‐1 Degradation, eNOS Uncoupling, and De‐differentiation of Endothelial Cells

Abstract

Introduction Caveolin-1 (Cav-1) knockout mice exhibit vascular abnormalities such as endothelial cell (EC) hypercellularity and fibrosis. We and others observed that lung ECs from Cav-1-/- mice exhibit a mesenchymal-like phenotype in culture suggesting Cav-1 is required to maintain differentiation of ECs. We also showed reduced Cav-1 expression in lung sections and HPAECs from patients with PAH suggesting EC Cav-1 degradation may play a role in pulmonary remodeling. The aim of the study was to determine whether chronic inflammatory lung injury (ALI) induces Cav-1 degradation and de-differentiation of ECs, and whether EC-specific Cav-1-/- mice exhibit EC hyperplasia and vascular remodeling. Methods: ALI was induced in wild-type (WT) and EC-specific Tie2.Cre;Cav-1-/- mice by exposure to nebulized E. coli LPS (10 mg/1 hr). After 96 hr, Cav-1 and eNOS expression and phosphorylation were quantified in lung lysates and histological sections. Results: LPS exposure of WT mice reduced Cav-1 expression compared to untreated WT mice, and the extent of Cav-1 depletion was similar to that observed in EC-Cav-1-/- (P ˂ 0.05; n= 3). Moreover, EC Cav-1 depletion in WT and EC-Cav-1-/- mouse lungs was associated with reduced eNOS dimerization and an increase in pSer1179-eNOS. Conclusion ALI reduced Cav-1 expression and promoted eNOS uncoupling suggesting Cav-1 degradation may play a significant role in the onset of inflammatory pulmonary vascular disease. Funding support: CNPq Fellowship - CsF/Brazil; P01 HL60678; R01EY019494.