title: Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-β-driven pulmonary vascular remodeling.
abstract: Endothelial cell (EC) activation and vascular injury are hallmark features of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Caveolin-1 (Cav-1) is highly expressed in pulmonary microvascular ECs and plays a key role in maintaining vascular homeostasis. The aim of this study was to determine if the lung inflammatory response toEscherichia colilipopolysaccharide (LPS) promotes priming of ECs via Cav-1 depletion and if this contributes to the onset of pulmonary vascular remodeling. To test the hypothesis that depletion of Cav-1 primes ECs to respond to profibrotic signals, C57BL6 wild-type (WT) mice (Tie2.Cre-;Cav1fl/fl) were exposed to nebulized LPS (10 mg; 1 h daily for 4 days) and compared with EC-specificCav1-/-(Tie2.Cre+;Cav1fl/fl). After 96 h of LPS exposure, total lung Cav-1 and bone morphogenetic protein receptor type II (BMPRII) expression were reduced in WT mice. Moreover, plasma albumin leakage, infiltration of immune cells, and levels of IL-6/IL-6R and transforming growth factor-β (TGF-β) were elevated in both LPS-treated WT andEC-Cav1-/-mice. Finally,EC-Cav1-/-mice exhibited a modest increase in microvascular thickness basally and even more so on exposure to LPS (96 h).EC-Cav1-/-mice and LPS-treated WT mice exhibited reduced BMPRII expression and endothelial nitric oxide synthase uncoupling, which along with increased TGF-β promoted TGFβRI-dependent SMAD-2/3 phosphorylation. Finally, human lung sections from patients with ARDS displayed reduced EC Cav-1 expression, elevated TGF-β levels, and severe pulmonary vascular remodeling. Thus EC Cav-1 depletion, oxidative stress-mediated reduction in BMPRII expression, and enhanced TGF-β-driven SMAD-2/3 signaling promote pulmonary vascular remodeling in inflamed lungs.
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Suellen D S
authors.identifier: 0000-0002-7654-1909
authors.initials: SDS
authors.lastname: Oliveira
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois.|Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Maricela
authors.initials: M
authors.lastname: Castellon
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Elliott
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois; rminsh@uic.edu.|Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
mesh_terms: D000199:Actins / Q000378:metabolism; D055371:Acute Lung Injury / Q000150:complications / Q000276:immunology / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D051242:Caveolin 1 / Q000378:metabolism*; D048430:Cell Shape / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides; D008168:Lung / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008954:Models, Biological; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D011651:Pulmonary Artery / Q000473:pathology; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000150:complications / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D051242:Caveolin 1; D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D052250:Nitric Oxide Synthase Type III; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: ARDS; TGF-β signaling; caveolin-1; endothelial dysfunction; vascular inflammation; vascular remodeling