on June 3, 2004
Published online before print June 3, 2004, doi: 10.1161/01.ATV.0000134705.39654.53
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Submitted on February 10, 2004
Accepted on May 26, 2004
Vasodilator-Stimulated Phosphoprotein Regulates Proliferation and Growth Inhibition by Nitric Oxide in Vascular Smooth Muscle Cells
Lihua Chen *;
From the Departments of Surgery (L.C., G.D., K.C., A.W.C.) and Pathology (S.A.C., D.F.B.-P.), University of Washington, Seattle; and Institut für Klinische Biochemie und Pathobiochemie (M.E., N.R.T., U.W.), Josef-Schneider-Strasse, Würzburg, Germany.
* To whom correspondence should be addressed. E-mail: lihua{at}u.washington.edu.
Objective--Vasodilator-stimulated phosphoprotein (VASP) was identified as a substrate for cGMP-dependent protein kinase (PKG) and cAMP-dependent protein kinase (PKA). It is preferentially phosphorylated at serine239 by PKG, whereas serine157 is a preferred phosphorylation site for PKA. In addition, serine157 is phosphorylated by PKC in response to serum. We have investigated the effects of VASP and VASP phosphorylation at serine157 and serine239 on smooth muscle cell (SMC) proliferation and nitric oxide (NO)-mediated growth inhibition.
Methods and Results--Aortic SMCs derived from VASP-deficient mice were transduced with retroviral vectors encoding either wild-type VASP or VASP mutants (S157A-VASP and S239A-VASP), in which serine157 and serine239, respectively, were replaced by a nonphosphorylatable amino acid, alanine. Expression of wt-VASP and S239A-VASP significantly increased proliferation, whereas expression of S157A-VASP was inhibitory. Expression of S239A-VASP rendered SMCs less sensitive to growth inhibition by the NO donor, S-nitroso-n-acetylpenicillamine, when compared with cells expressing wt-VASP. Similar effects were observed in cultured rat SMCs in which wt-VASP, S157A-VASP, and S239A-VASP were expressed.
Conclusions--Our data suggest that VASP phosphorylation at serine157 is required for the growth-stimulatory effect of VASP in SMCs, whereas VASP phosphorylation at serine239 is involved in the growth inhibitory effects of NO on SMCs.
Key words: vasodilator-stimulated phosphoprotein • smooth muscle cell growth • nitric oxide • phosphorylation • cell signaling
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