title: Twist1 controls lung vascular permeability and endotoxin-induced pulmonary edema by altering Tie2 expression.
abstract: Tight regulation of vascular permeability is necessary for normal development and deregulated vascular barrier function contributes to the pathogenesis of various diseases, including acute respiratory distress syndrome, cancer and inflammation. The angiopoietin (Ang)-Tie2 pathway is known to control vascular permeability. However, the mechanism by which the expression of Tie2 is regulated to control vascular permeability has not been fully elucidated. Here we show that transcription factor Twist1 modulates pulmonary vascular leakage by altering the expression of Tie2 in a context-dependent way. Twist1 knockdown in cultured human lung microvascular endothelial cells decreases Tie2 expression and phosphorylation and increases RhoA activity, which disrupts cell-cell junctional integrity and increases vascular permeability in vitro. In physiological conditions, where Ang1 is dominant, pulmonary vascular permeability is elevated in the Tie2-specific Twist1 knockout mice. However, depletion of Twist1 and resultant suppression of Tie2 expression prevent increase in vascular permeability in an endotoxin-induced lung injury model, where the balance of Angs shifts toward Ang2. These results suggest that Twist1-Tie2-Angs signaling is important for controlling vascular permeability and modulation of this mechanism may lead to the development of new therapeutic approaches for pulmonary edema and other diseases caused by abnormal vascular permeability.
authors.affiliation: 1 Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mammoto
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jiang
authors.forename: Amanda
authors.initials: A
authors.lastname: Jiang
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Lu
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Juan
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Akiko
authors.initials: A
authors.lastname: Mammoto
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D042787:Receptor, TIE-2 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D051879:Twist-Related Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D004731:Endotoxins; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D042787:Receptor, TIE-2
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