Abstract 311: TGFb/Smad3 Stimulation Drives Smooth Muscle Cell De-differentiation

Restenosis, or vessel re-narrowing, occurs in approximately 25-50% of arterial interventions involving balloon angioplasty due to the formation of a proliferative plaque in the vessel lumen termed neo-intimal hyperplasia. Arterial smooth muscle cells (SMCs) contribute to neo-intimal hyperplasia through a de-differentiation process that includes downregulation of their contractile gene expression and conversion to a phenotype that includes proliferation, migration, and matrix synthesis. Expression of TGFβ and its downstream signaling protein, Smad3, are greatly upregulated following vascular injury, including balloon angioplasty. Classically, TGFβ signaling has been shown to suppress SMC proliferation and migration in vitro, however, Smad3 overexpressing SMCs demonstrate enhanced proliferation and migration. Furthermore, overexpression of Smad3 in rat carotid arteries enhances neo-intimal hyperplasia following balloon angioplasty. These results lead us to hypothesize that TGFβ signaling, in the context of upregulated Smad3, drives SMC de-differentiation leading to enhanced cellular proliferation and migration. We utilized primary rat SMCs infected with adenovirus constructs overexpressing Smad3 or GFP control and performed gene expression microarrays 24 hours following TGFβ administration. We observed statistically significant (p