cAMP-dependent protein kinase inhibits the mitogenic action of vascular endothelial growth factor and fibroblast growth factor in capillary endothelial cells by blocking Raf activation
Journal
Journal of Cellular Biochemistry
Journal Volume
67
Journal Issue
3
Pages
353-366
Date Issued
1997
Author(s)
URI
Abstract
Proliferation of endothelial cells is regulated by angiogenic and antiangiogenic factors whose actions are mediated by complex interactions of multiple signaling pathways. Both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) stimulate cell proliferation and activate the mitogen-activated protein kinase (MAPK) cascade in bovine brain capillary endothelial (BBE) cells. We have extended these findings to show that both mitogens activate MAPK via stimulation of Raf-1. Activation of Raf/MAPK is inhibited by increasing intracellular cAMP levels pharmacologically or via stimulation of endogenously expressed β-adrenergic receptors. Both VEGF- and bFGF-induced Raf-1 activity are blocked in the presence of forskolin or 8-bromo-cAMP by 80%. The actions of increased cAMP appear to be mediated by cAMP-dependent protein kinase (PKA), since treatment with H-89, a the specific inhibitor of PKA, reversed the inhibitory effect of elevated cAMP levels on mitogen-induced cell proliferation and Raf/MAPK activation. Moreover, elevations in cAMP/PKA activity inhibit mitogen- induced cell proliferation. These findings demonstrate, in cultured endothelial cells, that the cAMP/PKA signaling pathway is potentially an important physiological inhibitor of mitogen activation of the MAPK cascade and cell proliferation.
Subjects
Endothelial cells; MAPK; PKA; Raf-1
Other Subjects
8 bromo cyclic amp; basic fibroblast growth factor; cyclic amp dependent protein kinase; fibroblast growth factor; forskolin; mitogen activated protein kinase; vasculotropin; animal cell; article; capillary endothelium; cattle; cell proliferation; endothelium cell; enzyme inhibition; inhibition kinetics; mitogenesis; molecular interaction; nonhuman; priority journal; 1-Methyl-3-isobutylxanthine; 8-Bromo Cyclic Adenosine Monophosphate; Adenylate Cyclase; Animals; Brain; Ca(2+)-Calmodulin Dependent Protein Kinase; Capillaries; Cattle; Cell Division; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Endothelial Growth Factors; Endothelium, Vascular; Enzyme Inhibitors; Fibroblast Growth Factor 2; Forskolin; Isoproterenol; Isoquinolines; Lymphokines; Phosphodiesterase Inhibitors; Proto-Oncogene Proteins c-raf; Signal Transduction; Sulfonamides; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
Type
journal article