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Endothelial to Mesenchymal Transition Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension.

Good, RB, Gilbane, AJ, Trinder, SL, Denton, CP, Coghlan, G, Abraham, DJ and Holmes, AM (2015) Endothelial to Mesenchymal Transition Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension. Am J Pathol, 185 (7). pp. 1850-1858.

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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.

Item Type: Article
Divisions : Surrey research (other units)
Authors :
Good, RB
Gilbane, AJ
Denton, CP
Coghlan, G
Abraham, DJ
Holmes, AM
Date : July 2015
DOI : 10.1016/j.ajpath.2015.03.019
Uncontrolled Keywords : Animals, Cells, Cultured, Coculture Techniques, Cytokines, Endothelial Cells, Endothelium, Epithelial-Mesenchymal Transition, Humans, Hypertension, Pulmonary, Lung, Mice, Pulmonary Artery, Up-Regulation, Vascular Remodeling
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:44
Last Modified : 24 Jan 2020 19:58

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