title: EG-VEGF, BV8, and their receptor expression in human bronchi and their modification in cystic fibrosis: Impact of CFTR mutation (delF508).
abstract: Enhanced lung angiogenesis has been reported in cystic fibrosis (CF). Recently, two highly homologous ligands, endocrine gland vascular endothelial growth factor (EG-VEGF) and mammalian Bv8, have been described as new angiogenic factors. Both ligands bind and activate two closely related G protein-coupled receptors, the prokineticin receptor (PROKR) 1 and 2. Yet, the expression, regulation, and potential role of EG-VEGF, BV8, and their receptors in normal and CF lung are still unknown. The expression of the receptors and their ligands was examined using molecular, biochemical, and immunocytochemistry analyses in lungs obtained from CF patients vs. control and in normal and CF bronchial epithelial cells. Cystic fibrosis transmembrane conductance regulator (CFTR) activity was evaluated in relation to both ligands, and concentrations of EG-VEGF were measured by ELISA. At the mRNA level, EG-VEGF, BV8, and PROKR2 gene expression was, respectively, approximately five, four, and two times higher in CF lungs compared with the controls. At the cellular level, both the ligands and their receptors showed elevated expressions in the CF condition. Similar results were observed at the protein level. The EG-VEGF secretion was apical and was approximately two times higher in CF compared with the normal epithelial cells. This secretion was increased following the inhibition of CFTR chloride channel activity. More importantly, EG-VEGF and BV8 increased the intracellular concentration of Ca(2+) and cAMP and stimulated CFTR-chloride channel activity. Altogether, these data suggest local roles for epithelial BV8 and EG-VEGF in the CF airway peribronchial vascular remodeling and highlighted the role of CFTR activity in both ligand biosynthesis and secretion.
authors.affiliation: Centre National de la Recherche Scientifique, LCBM-UMR 5249, Grenoble, France; Commissariat à l'Energie Atomique, DSV-iRTSV, Grenoble, France; Grenoble Alpes Université, Grenoble, France;
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chauvet
authors.affiliation: Commissariat à l'Energie Atomique, DSV-iRTSV, Grenoble, France; Grenoble Alpes Université, Grenoble, France; Institut National de la Santé et de la Recherche Médicale, U1036, Grenoble, France; and.
authors.forename: Wael
authors.initials: W
authors.lastname: Traboulsi
authors.affiliation: Commissariat à l'Energie Atomique, DSV-iRTSV, Grenoble, France; Grenoble Alpes Université, Grenoble, France; Institut National de la Santé et de la Recherche Médicale, U1036, Grenoble, France; and.
authors.forename: Laura
authors.initials: L
authors.lastname: Thevenon
authors.affiliation: Centre National de la Recherche Scientifique, LCBM-UMR 5249, Grenoble, France; Commissariat à l'Energie Atomique, DSV-iRTSV, Grenoble, France; Grenoble Alpes Université, Grenoble, France;
authors.forename: Amal
authors.initials: A
authors.lastname: Kouadri
authors.affiliation: Commissariat à l'Energie Atomique, DSV-iRTSV, Grenoble, France; Grenoble Alpes Université, Grenoble, France; Institut National de la Santé et de la Recherche Médicale, U1036, Grenoble, France; and.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.affiliation: Centre de Ressources et de Compétences pour la Mucoviscidose, Clinique Universitaire de Pneumologie-Pole Thorax et Vaisseaux, CHU de Grenoble, France.
authors.forename: Boubou
authors.initials: B
authors.lastname: Camara
authors.affiliation: Commissariat à l'Energie Atomique, DSV-iRTSV, Grenoble, France; Grenoble Alpes Université, Grenoble, France; Institut National de la Santé et de la Recherche Médicale, U1036, Grenoble, France; and.
authors.forename: Nadia
authors.initials: N
authors.lastname: Alfaidy
authors.affiliation: Centre National de la Recherche Scientifique, LCBM-UMR 5249, Grenoble, France; Commissariat à l'Energie Atomique, DSV-iRTSV, Grenoble, France; Grenoble Alpes Université, Grenoble, France; mohamed.benharouga@cea.fr.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benharouga
mesh_terms: D000328:Adult; D000368:Aged; D020013:Calcium Signaling; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: C505032:CFTR protein, human; D002712:Chlorides; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human; C470837:PROKR1 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: BV8/endocrine gland vascular endothelial growth factor; cystic fibrosis transmembrane conductance regulator; lung angiogenesis; prokineticin receptors