VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors

Laure Favot; Thérèse Keravis; Vincent Holl; Alain Le Bec; Claire Lugnier

doi:10.1160/TH03-02-0084

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(02): 334-343
DOI: 10.1160/TH03-02-0084

Vascular Development and Vessel Remodelling

Schattauer GmbH

VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors

Laure Favot

¹Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, CNRS UHR 7034 Université Louis Pasteur de Strasbourg, Illkirch, France

,

Thérèse Keravis

¹Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, CNRS UHR 7034 Université Louis Pasteur de Strasbourg, Illkirch, France

,

Vincent Holl

²Laboratoire de Cancérologie Expérimentale et de Radiobiologie (LCER), Institut de Recherche contre les Cancers de l’Appareil Digestif (IRCAD), Hôpital Civil, Strasbourg, France

,

Alain Le Bec

¹Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, CNRS UHR 7034 Université Louis Pasteur de Strasbourg, Illkirch, France

,

Claire Lugnier

¹Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, CNRS UHR 7034 Université Louis Pasteur de Strasbourg, Illkirch, France

› Author Affiliations

Abstract

Summary

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 µM), PDE2 selective inhibitor, and RP73401 (10 µM), 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 µM); 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.

Keywords

Angiogenesis and inhibitors - cell proliferation - cAMP phosphodiesterase - endothelial cell - VEGF

Full Text

References

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