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.