Adenovirus-mediated Intraarterial delivery of PTEN inhibits neointimal hyperplasia

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.