Adenovirus-Mediated Intraarterial Delivery of PTEN Inhibits Neointimal Hyperplasia

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Abstract
Objective— Phosphoinositide (PI) 3-kinase promotes vascular smooth muscle cell (VSMC) responses necessary for neointimal hyperplasia. We recently demonstrated that the inositol 3-phosphatase PTEN is expressed in VSMCs and that its overexpression inhibits these cellular responses. The purpose of this study was to determine the effects of adenovirus-mediated overexpression of PTEN on neointimal hyperplasia in vivo in the rat carotid injury model. Methods and Results— Rat carotid arteries were balloon-injured and treated with a recombinant control adenovirus (AdEV) (n=6), an adenovirus encoding wild-type PTEN (AdPTEN) (n=8), or phosphate-buffered saline (sham) (n=5). Injured vessels demonstrated PTEN overexpression by Western blotting and immunohistochemistry after AdPTEN treatment. Neointimal hyperplasia was assessed 2 weeks after balloon injury and adenovirus administration. Compared with controls, AdPTEN treatment significantly decreased neointimal area and percent stenosis. To investigate the mechanisms of action of AdPTEN, vessels were harvested 3 days after balloon injury and virus infection. AdPTEN significantly increased medial cell apoptosis while decreasing proliferation of the remaining viable cells. Conclusions— PTEN overexpression potently inhibits neointimal hyperplasia through induction of apoptosis and inhibition of medial cell proliferation. These findings suggest that modulation of PTEN expression or activity may be a viable approach to treat neointimal hyperplasia.