Abstract

Purpose TGFβ is a powerful regulator of the cardiovascular system. The Smad protein family transduces the TGFβ signal and has been implicated in the development of intimal hyperplasia(IH)/restenosis. In this study, we explore the role of the receptor-regulated Smad3 and the inhibitory Smad7 in restenosis following vascular injury. Methods & Results Adenoviral vectors that express LacZ, Smad3, or Smad7 were delivered via intra-luminal perfusion immediately following balloon angioplasty of rat carotid arteries. At a dosage of 2.5x109 pfu, over 80% of medial smooth muscle cells (SMCs) became infected with transgene expression persisting for up to 4 weeks. Compared to animals receiving a control vector, AdSmad3 resulted in a thicker neointima, while AdSmad7 decreased IH. At 14 days post-injury, evaluation of SMC proliferation revealed increased PCNA+ SMCs following Smad3 infection but decreased PCNA staining following AdSmad7, suggesting that Smad3 stimulates SMC proliferation and thus the formation of IH. Moreover, AdSmad3 treatment was accompanied by increased SMC matrix protein production. However, despite a larger neointima, the lumen of AdSmad3-treated arteries was preserved and accompanied by expansion of the external elastic lamina, indicating a role for Smad3 in adaptive vascular remodeling. Blocking Smad3 with Smad7 overexpression also limited SMC matrix protein production and attenuated lumen loss in balloon injured arteries, although no effect on vascular remodeling was observed. Conclusions These finding suggest that the TGFβ/Smad pathway plays a dual role in the development of restenosis following angioplasty.

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