All forms of arterial interventions injure the diseased vessel and induce a response to that injury. The response to injury is a multifactorial process and results in a reduction in lumen size either by vessel remodeling or by intimal thickening. Proliferation and migration of vascular smooth muscle cells (SMC) significantly contribute to intimal thickening and are the predominant mechanisms of in-stent restenosis. However, despite major advances in vascular biology, the mechanisms ultimately regulating uncontrolled SMC replication during neointima formation are largely unknown thus compounding the challenge of successful clinical treatment. In the absence of vascular trauma, the mature blood vessel remains a highly quiescent tissue with SMC exhibiting extremely low daily replication rates (0.05% per day). The focus of the studies in our laboratory has been to identify mechanisms of endogenous SMC growth inhibition. The possibility of targeting such endogenous mechanisms would open up new perspectives for a targeted molecular approach to reducing lesion formation following vascular interventions. Our published and preliminary data will demonstrate differentiated SMC in mature arteries produce and deposit heparan sulfate- rich perlecan into the SMC basement membrane. Perlecan-SMC interactions result in increased activity of PTEN thus contributing to SMC quiescence in the uninjured artery. However, vascular injury (e.g. balloon angioplasty, stent placement) results in local perlecan proteolysis, decreased PTEN activity, and rapid, autonomous cell growth. Our central thesis for this proposal is that combined adenoviral-mediated overexpression of the tumor suppressor PTEN and the heparan sulfate-rich subdomains of perlecan, two endogenous SMC growth inhibitors, using a localized, stent-based delivery of adenovirus will effectively inhibit in-stent neointima formation. The first Aim is proposed to verify the efficiency of the adenovirus delivery method and to test our central hypothesis in an in vitro system. The second Aim is proposed to test our central hypothesis in an in vivo stent deployment system using the optimal coating formulation determined in Aim One that provides the highest level of coating stability following stent deployment combined with the greatest degree of SMC growth inhibition. Our proposed experimental approach should yield highly significant, new information regarding a unique approach to reducing in-stent restenosis.

R21EB003999

2006-03-01

2008-02-29