Smooth muscle cell-specific Tgfbr1 deficiency attenuates neointimal hyperplasia but promotes an undesired vascular phenotype for injured arteries.

Neointimal hyperplasia (NIH) and inward wall remodeling cause arterial restenosis and failure of bypass vein grafts. Previous studies from our group suggest that transforming growth factor (TGF) β promotes these pathologies via regulating cell kinetics at the early stage and matrix metabolism at the late stage. Although these temporal TGFβ effects may result from its signaling in different cell groups, the responsible cell type has not been identified. In the current study, we evaluated the effect of smooth muscle cell (SMC)-specific TGFβ signaling through its type I receptor TGFBR1 on NIH and wall remodeling of the injured femoral arteries (FAs). An inducible Cre/loxP system was employed to delete SMC Tgfbr1 (Tgfbr1). Mice not carrying the Cre allele (Tgfbr1) served as controls. The injured FAs were evaluated on d3, d7, and d28 postoperatively. Tgfbr1 attenuated NIH by 92%, but had insignificant influence on arterial caliber when compared with Tgfbr1 controls on d28. This attenuation correlated with greater cellularity and reduced collagen content. Compared with Tgfbr1 FAs, however, Tgfbr1 FAs exhibited persistent neointimal cell proliferation and cell apoptosis, with both events at a greater rate on d28. Tgfbr1 FAs additionally contained fewer SMCs and more inflammatory infiltrates in the neointima and displayed a thicker adventitia than did Tgfbr1 FAs. More MMP9 proteins were detected in the adventitia of Tgfbr1 FAs than in that of Tgfbr1 controls. Our results suggest that disruption of SMC Tgfbr1 inhibits arterial NIH in the short term, but the overall vascular phenotype may not favor long-term performance of the injured arteries.