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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:745.)
© 2002 American Heart Association, Inc.

Vascular Biology

Inhibition of Vascular Smooth Muscle Cell Proliferation, Migration, and Survival by the Tumor Suppressor Protein PTEN

Jianhua Huang; Christopher D. Kontos

From the Department of Medicine (J.H., C.D.K.), Division of Cardiology; and Department of Pharmacology and Cancer Biology (C.D.K.), Duke University Medical Center, Durham, NC.

Correspondence to Christopher D. Kontos, MD, Box 3629 Duke University Medical Center, Durham, NC 27710. E-mail cdkontos@ duke.edu

Phosphatidylinositol (PI) 3-kinase signaling regulates numerous cellular processes, including proliferation, migration, and survival, which are required for neointimal hyperplasia and restenosis. The effectors of PI 3-kinase are activated by the phospholipid products of PI 3-kinase. In this report, we investigated the hypothesis that overexpression of the tumor suppressor protein PTEN, an inositol phosphatase specific for the products of PI 3-kinase, would inhibit the vascular smooth muscle cell (VSMC) responses necessary for neointimal hyperplasia and restenosis. Effects of PTEN were assessed in primary rabbit VSMCs after overexpression with a recombinant adenovirus and compared with uninfected or control virus-infected cells. PTEN was expressed endogenously in VSMCs, and PTEN overexpression inhibited PDGF-induced phosphorylation of p70^s6k, Akt, and glycogen synthase kinase-3- and -ß but not ERK1 or -2. Overexpression of PTEN significantly inhibited both basal and PDGF-mediated VSMC proliferation and migration, the latter possibly due in part to downregulation of focal adhesion kinase. Moreover, PTEN overexpression induced cleavage of caspase-3 and significantly increased apoptosis compared with control cells. Taken together, these results demonstrate that PTEN overexpression potently inhibits the VSMC responses required for neointimal hyperplasia and restenosis. Adenovirus-expressed PTEN may therefore provide a useful tool for the local treatment of these and other vascular proliferative disorders.

Key Words: PTEN • vascular smooth muscle cell • phosphatidylinositol 3-kinase • p70^s6k • neointimal hyperplasia

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