VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors.
Migration and proliferation of endothelial cells in response to VEGF play an important role in angiogenesis associated to pathologies such as atherosclerosis, diabetes and tumor development. Elevation of cAMP in endothelial cells has been shown to inhibit growth factor-induced proliferation. Our hypothesis was that inactivation of cAMP-specific phosphodiesterases (PDEs) would inhibit angiogenesis. The purpose of this study was to evaluate the effect of PDE inhibitors on in vitro and in vivo angiogenesis, using human umbilical vein endothelial cell (HUVEC) and chick chorioallantoic membrane (CAM) models respectively. Here, we report that: 1) PDE2, PDE3, PDE4 and PDE5 are expressed in HUVEC; 2) EHNA (20 microM), PDE2 selective inhibitor, and RP73401 (10 microM), PDE4 selective inhibitor, are able to increase the intracellular cAMP level in HUVEC; 3) EHNA and RP73401 are able to inhibit proliferation, cell cycle progression and migration of HUVEC stimulated by VEGF; 4) these in vitro effects can be mimic by treating HUVEC with the cAMP analogue, 8-Br-cAMP (600 microM); 5) only the association of EHNA and RP73401 inhibits in vivo angiogenesis, indicating that both migration and proliferation must be inhibited. These data strongly suggest that PDE2 and PDE4 represent new potential therapeutic targets in pathological angiogenesis.
Favot
Laure
L
Pharmacologie et Physicochimie des Interactions Cellulaires et Moléculaires, CNRS UMR 7034 Université Louis Pasteur de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, Illkirch, 67401, France. claire@aspirine.u-strasbg.fr
Keravis
Thérèse
T
Holl
Vincent
V
Le Bec
Alain
A
Lugnier
Claire
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000482:Allantois / Q000098:blood supply; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D000242:Cyclic AMP / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D001549:Benzamides; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D015124:8-Bromo Cyclic Adenosine Monophosphate; C010192:9-(2-hydroxy-3-nonyl)adenine; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517275:PDE2A protein, human; D000225:Adenine; C087566:piclamilast