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BAY 41-2272 (BAY), a stimulator of soluble guanylyl cyclase, increases cyclic nucleotides and inhibits proliferation of vascular smooth muscle cells (VSMCs). In this study, we elucidated mechanisms of action of BAY in its regulation of vasodilator-stimulated phosphoprotein (VASP) with an emphasis on VSMC phosphodiesterases (PDEs). BAY alone increased phosphorylation of VASP(Ser239) and VASP(Ser157), respective indicators of PKG and PKA signaling. IBMX, a non-selective inhibitor of PDEs, had no effect on BAY-induced phosphorylation at VASP(Ser239) but inhibited phosphorylation at VASP(Ser157). Selective inhibitors of PDE3 or PDE4 attenuated BAY-mediated increases at VASP(Ser239) and VASP(Ser157), whereas PDE5 inhibition potentiated BAY-mediated increases only at VASP(Ser157). In comparison, 8Br-cGMP increased phosphorylation at VASP(Ser239) and VASP(Ser157) which were not affected by selective PDE inhibitors. In the presence of 8Br-cAMP, inhibition of either PDE4 or PDE5 decreased VASP(Ser239) phosphorylation and inhibition of PDE3 increased phosphorylation at VASP(Ser239), while inhibition of PDE3 or PDE4 increased and PDE5 inhibition had no effect on VASP(Ser157) phosphorylation. These findings demonstrate that BAY operates via cAMP and cGMP along with regulation by PDEs to phosphorylate VASP in VSMCs and that the mechanism of action of BAY in VSMCs is different from that of direct cyclic nucleotide analogs with respect to VASP phosphorylation and the involvement of PDEs. Given a role for VASP as a critical cytoskeletal protein, these findings provide evidence for BAY as a regulator of VSMC growth and a potential therapeutic agent against vasculoproliferative disorders.

Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells