SYNERGISTIC INHIBITION OF VASCULAR SMOOTH-MUSCLE CELL-MIGRATION BY PHOSPHODIESTERASE-3 AND PHOSPHODIESTERASE-4 INHIBITORS

Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze cAMP or cGMP and terminate their signaling. Two important families of PDEs that regula te cAMP signaling in cardiovascular tissues are the cGMP-inhibited PDE s (PDE3) and the cAMP-specific PDEs (PDE4). In this study, we have use d a combination of an in vitro motility assay and a sensitive method f or the measurement of cAMP in order to determine the relative roles of PDE3 and of PDE4 in the regulation of cAMP-mediated inhibition of VSM C migration. Our data demonstrate that forskolin, an activator of aden ylyl cyclases, causes concentration-dependent inhibition of platelet-d erived growth factor-induced VSMC mi,oration. Incubation of cultured V SMCs with a PDE4-selective inhibitor, Ro 20-1724, markedly potentiated both the antimigratory effect and the increase in cAMP caused by fors kolin. Cilostamide, a PDE3-selective compound, did not affect either t he antimigratory activity of forskolin or its ability to increase cAMP . Cilostamide and Ro 20-1724 interacted synergistically to potentiate the inhibition of VSMC migration by forskolin and caused a supra-addit ive increase in cAMP. These data are consistent with an important role for both PDE3 and PDE4 in the regulation of cAMP-mediated inhibition of VSMC migration.