TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation

Stenosis is a critical problemin the long-term efficacy of tissue-engineered vascular grafts (TEVGs). We previously showed that host monocyte infiltration and activation within the graft drives stenosis and that TGF-beta receptor 1 (TGF-beta R1) inhibition can prevent it, but the latter effect was attributed primarily to inhibition of mesenchymal cell expansion. In this study, we assessed the effects of TGF-beta R1 inhibition on the host monocytes. Biodegradable TEVGs were implanted as inferior vena cava interposition conduits in 2 groups of C57BL/6mice (n = 25/group): unseeded grafts and unseeded grafts with TGF-beta R1 inhibitor systemic treatment for the first 2 wk. The TGF-beta R1 inhibitor treatment effectively improved TEVG patency at 6mo compared to the untreated control group (91.7 vs. 48%, P < 0.001), which is associated with a reduction in classic activation of mononuclear phagocytes. Consistent with these findings, the addition of rTGF-beta to LPS/IFN-gamma-stimulated monocytes enhanced secretion of inflammatory cytokines TNF-alpha, IL-12, and IL-6; this effect was blocked by TGF-beta R1 inhibition (P < 0.0001). These findings suggest that the TGF-beta signaling pathway contributes to TEVG stenosis by inducing classic activation of host monocytes. Furthermore, blocking monocyte activation by TGF-beta R1 inhibition provides a viable strategy for preventingTEVGstenosiswhilemaintainingneotissue formation.-Lee, Y.-U., de Dios Ruiz-Rosado, J., Mahler, N., Best, C. A., Tara, S., Yi, T., Shoji, T., Sugiura, T., Lee, A. Y., Robledo-Avila, F., Hibino, N., Pober, J. S., Shinoka, T., Partida-Sanchez, S., Breuer, C. K. TGF-beta receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation.