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

Stenosis is a critical problem in 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‐β receptor 1 (TGF‐βR1) 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‐βR1 inhibition on the host monocytes. Biodegradable TEVGs were implanted as inferior vena cava interposition conduits in 2 groups of C57BL/6 mice ( n = 25/group): unseeded grafts and unseeded grafts with TGF‐βR1 inhibitor systemic treatment for the first 2 wk. The TGF‐βR1 inhibitor treatment effectively improved TEVG patency at 6 mo 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‐β to LPS/IFN‐γ‐stimulated monocytes enhanced secretion of inflammatory cytokines TNF‐α, IL‐12, and IL‐6; this effect was blocked by TGF‐βR1 inhibition ( P < 0.0001). These findings suggest that the TGF‐β signaling pathway contributes to TEVG stenosis by inducing classic activation of host monocytes. Furthermore, blocking monocyte activation by TGF‐βR1 inhibition provides a viable strategy for preventing TEVG stenosis while maintaining neotissue 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‐β receptor 1 inhibition prevents stenosis of tissue‐engineered vascular grafts by reducing host mononuclear phagocyte activation. FASEB J. 30, 2627‐2636 (2016). www.fasebj.org