title: Endothelial to Mesenchymal Transition Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial cell dysfunction and vascular remodeling. Normally, the endothelium forms an integral cellular barrier to regulate vascular homeostasis. During embryogenesis endothelial cells exhibit substantial plasticity that contribute to cardiac development by undergoing endothelial-to-mesenchymal transition (EndoMT). We determined the presence of EndoMT in the pulmonary vasculature in vivo and the functional effects on pulmonary artery endothelial cells (PAECs) undergoing EndoMT in vitro. Histologic assessment of patients with systemic sclerosis-associated PAH and the hypoxia/SU5416 mouse model identified the presence von Willebrand factor/α-smooth muscle actin-positive endothelial cells in up to 5% of pulmonary vessels. Induced EndoMT in PAECs by inflammatory cytokines IL-1β, tumor necrosis factor α, and transforming growth factor β led to actin cytoskeleton reorganization and the development of a mesenchymal morphology. Induced EndoMT cells exhibited up-regulation of mesenchymal markers, including collagen type I and α-smooth muscle actin, and a reduction in endothelial cell and junctional proteins, including von Willebrand factor, CD31, occludin, and vascular endothelial-cadherin. Induced EndoMT monolayers failed to form viable biological barriers and induced enhanced leak in co-culture with PAECs. Induced EndoMT cells secreted significantly elevated proinflammatory cytokines, including IL-6, IL-8, and tumor necrosis factor α, and supported higher immune transendothelial migration compared with PAECs. These findings suggest that EndoMT may contribute to the development of PAH.
authors.affiliation: Division of Medicine, University College London Medical School, Royal Free Campus, London, United Kingdom.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Good
authors.affiliation: Division of Medicine, University College London Medical School, Royal Free Campus, London, United Kingdom.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Gilbane
authors.affiliation: Division of Medicine, University College London Medical School, Royal Free Campus, London, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Trinder
authors.affiliation: Division of Medicine, University College London Medical School, Royal Free Campus, London, United Kingdom.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.affiliation: National Pulmonary Hypertension Service, Royal Free Hospital National Health Service Foundation Trust, London, United Kingdom.
authors.forename: Gerry
authors.initials: G
authors.lastname: Coghlan
authors.affiliation: Division of Medicine, University College London Medical School, Royal Free Campus, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Abraham
authors.affiliation: Division of Medicine, University College London Medical School, Royal Free Campus, London, United Kingdom. Electronic address: alan.holmes@ucl.ac.uk.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Holmes
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004727:Endothelium / Q000503:physiopathology; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply / Q000473:pathology; D051379:Mice; D011651:Pulmonary Artery / Q000166:cytology / Q000503:physiopathology; D015854:Up-Regulation; D066253:Vascular Remodeling
chemical_list: D016207:Cytokines