Abstract 369: SMC-Specific Tgfbr1 Deficiency Inhibits Neointimal Hyperplasia In Injured Arteries

Abstract

Introduction: Stented arteries and vein bypass grafts fail due to neointimal hyperplasia (NIH). Transforming growth factor (TGF)-β has been identified as a driving force for this pathology. Our previous studies suggest that TGFβ contributes to NIH via regulating cell kinetics at early stage and matrix metabolism at late stage. While this differential TGFβ effect may result from its signaling in different cell-groups, the dominant cellular effectors at each stage remain to be determined. In this study, we evaluated the effect of TGFβ signaling in smooth muscle cell (SMCs) on NIH in injured arteries. Methods and results: An inducible Cre/loxP system driven by a Myh11 promoter was employed to delete SMC-specific Tgfbr1 ( Tgfbr1 iko ). Male mice at 10 weeks of age were used in the study and those not carrying the Cre allele ( Tgfbr1 f/f ) served as controls. On the following day of the last tamoxifen injection (day 0, d0), animals received transmural mechanical injury to induce NIH in femoral arteries (FAs). By d28, Tgfbr1 iko attenuated NIH by 90% compared with Tgfbr1 f/f . However, the injured Tgfbr1 iko FAs contained fewer α-actin positive cells and displayed significantly higher rate of cell proliferation and apoptosis with less matrix deposition than Tgfbr1 f/f controls in neointima. Intense inflammatory infiltration was detected in adventitia of Tgfbr1 iko , but not Tgfbr1 f/f , FAs. To explore mechanisms underlying these cellular events, we examined the growth of SMCs explanted from Tgfbr1 iko and Tgfbr1 f/f aortas and assessed their response to TGFβ stimulation. As expected, TGFβ1 inhibited cell growth and induced expression of collagen and elastin in Tgfbr1 f/f SMCs. In contrast, Tgfbr1 iko SMCs were resistant to TGF-β1 stimulation, evidenced by insignificant change in levels of these variables. Intriguingly, Tgfbr1 iko SMCs grew significantly slower than Tgfbr1 f/f SMCs under standard culture condition. Daily refreshment of culture medium doubled the population-growth of Tgfbr1 iko , but not Tgfbr1 f/f , SMCs, indicating production of growth inhibitory factor(s) by Tgfbr1 iko SMCs. Conclusion: Blockade of SMC-specific TGFBR1 activity inhibits NIH in a short-term, but, the resultant phenotype may not favor long-term performance of the injured arteries.