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

Abstract

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 TGF β 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 TGF β 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 ^iko ). Mice not carrying the Cre allele ( Tgfbr1 ^f/f ) served as controls. The injured FAs were evaluated on d3, d7, and d28 postoperatively. Tgfbr1 ^iko attenuated NIH by 92%, but had insignificant influence on arterial caliber when compared with Tgfbr1 ^f/f controls on d28. This attenuation correlated with greater cellularity and reduced collagen content. Compared with Tgfbr1 ^f/f FAs, however, Tgfbr1 ^iko FAs exhibited persistent neointimal cell proliferation and cell apoptosis, with both events at a greater rate on d28. Tgfbr1 ^iko FAs additionally contained fewer SMCs and more inflammatory infiltrates in the neointima and displayed a thicker adventitia than did Tgfbr1 ^f/f FAs. More MMP9 proteins were detected in the adventitia of Tgfbr1 ^iko FAs than in that of Tgfbr1 ^f/f 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.