Abstract
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<0.05) upregulation of 145 genes and downregulation of 76 genes by more than 3-fold. GO term analysis revealed that genes involved in embryonic tissue development (41 genes) and stem/progenitor cell differentiation (27 genes) were significantly enriched in TGFβ/Smad3 stimulated cells. Confirmatory qRT-PCR demonstrated that the contractile genes SM-MHC, smooth muscle actin, and calponin were significantly downregulated -6.3, -2.7 and -2.1 fold, respectively. In contrast, stem/developmental related genes Cxcr4, Cd34, Wnt11, Wnt2b and IL11 were significantly upregulated by 105.2, 22.3, 11.5, 14.0, and 12.5 fold, respectively. These results strongly suggest that TGFβ/Smad3 stimulation is a powerful de-differentiation signal in SMCs and plays an important role in the development of neo-intimal hyperplasia.
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