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Pulmonary Vascular Inflammation Promotes Caveolin‐1 Degradation, eNOS Uncoupling, and De‐differentiation of Endothelial Cells
Author(s) -
Oliveira Suellen,
Castellon Maricela,
Bonini Marcelo,
Elliott Michael,
Minshall Richard
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.863.13
Subject(s) - enos , caveolin 1 , lung , inflammation , knockout mouse , chemistry , endocrinology , medicine , nitric oxide , nitric oxide synthase , receptor
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.