title: CFTR dysfunction induces vascular endothelial growth factor synthesis in airway epithelium.
abstract: Peribronchial angiogenesis may occur in cystic fibrosis and vascular endothelial growth factor (VEGF)-A regulates angiogenesis in airways. Peribronchial vascularity and VEGF-A expression were examined using immunocytochemistry and morphometric analysis in lung sections obtained in 10 cystic fibrosis patients at transplantation versus 10 control nonsmokers, and in two strains of Cftr-deficient mice versus wild-type littermates. Airway epithelial NCI-H292 cells and primary cultures of noncystic fibrosis human airway epithelial cells were treated with cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors (CFTR-inh(172) or PPQ-102) or transfected with a CFTR small interfering (si)RNA with or without a selective epidermal growth factor receptor tyrosine kinase inhibitor. Concentrations of VEGF-A and phosphorylated epidermal growth factor receptor were measured by ELISA. Peribronchial vascularity was increased in cystic fibrosis patients, but not in Cftr-deficient mice. VEGF-A immunostaining was localised to airway epithelium and was increased in cystic fibrosis patients and in Cftr-deficient mice. In cultured airway epithelial cells, treatment with CFTR inhibitors or transfection with CFTR siRNA induced a twofold increase in VEGF-A production. CFTR inhibitors triggered epidermal growth factor receptor phosphorylation that was required for VEGF-A synthesis. Cystic fibrosis airways at transplantation showed increased peribronchial vascularity and epithelial VEGF-A expression. CFTR dysfunction triggered epithelial synthesis of VEGF-A, which may contribute to vascular remodelling.
authors.affiliation: Sorbonne Paris Cité, Paris.
authors.forename: Clémence
authors.initials: C
authors.lastname: Martin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Coolen
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: Wu
authors.forename: Guiti
authors.initials: G
authors.lastname: Thévenot
authors.forename: Lhousseine
authors.initials: L
authors.lastname: Touqui
authors.forename: Virginie
authors.initials: V
authors.lastname: Prulière-Escabasse
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Papon
authors.forename: André
authors.initials: A
authors.lastname: Coste
authors.forename: Estelle
authors.initials: E
authors.lastname: Escudier
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dusser
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fajac
authors.forename: Pierre-Régis
authors.initials: PR
authors.lastname: Burgel
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001980:Bronchi / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000235:genetics / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D004848:Epithelium / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000098:blood supply; D051379:Mice; D018181:Mice, Inbred CFTR; D008822:Mice, Transgenic; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D014132:Trachea / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C505032:CFTR protein, human; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D066246:ErbB Receptors