Tenascin-C synthesized in both donor grafts and recipients accelerates artery graft stenosis

Abstract

Objective: Tenascin-C, an extracellular matrix glycoprotein, is thought to play an important role in neointimal hyperplasia of artery bypass grafts. In this study, the direct contribution of tenascin-C to neointimal hyperplasia of free artery grafts and the origin of tenascin-C-producing cells were examined using tenascin-C transgenic mice. Methods and results: Abdominal aorta-to-carotid artery interposition grafting was performed in mice. When grafts from wild-type mice were transplanted to wild-type, neointimal hyperplasia was observed in the grafts at days 14 and 28. Immunohistochemical staining showed strong expression of tenascin-C in the media and neointima of the grafts. Much less neointimal hyperplasia was seen when grafts from tenascin-C-deficient mice were transplanted to tenascin-C-deficient mice. In tenascin-C-deficient grafts transplanted to wild-type mice, tenascin-C deposition was observed only in the neointima. In the reverse combination, deposition was seen in the media and neointima. The source of the tenascin-C-producing cells was analyzed using heterozygous mice that identically express both tenascin-C and LacZ. While LacZ-positive cells were seen only in the neointima of artery grafts from wild-type transplanted to mutant mice, positive cells were detected in both the neointima and media in grafts from mutant to wild-type mice. Conclusions: We presented direct evidence that tenascin-C is a crucial molecule in neointimal hyperplasia in free artery grafts, and that tenascin-C-producing cells are derived from both donor grafts and recipients.

Extra cellular matrix remodelling after heterotopic rat heart transplantation: gene expression profiling and involvement of ED-A+ fibronectin, alpha-smooth muscle actin and B+ tenascin-C in chronic cardiac allograft rejection

“…For Tn-C, a role for the development of classic atherosclerosis, angiogenesis and the recruitment of MyoFb in diseased cardiac tissue has been demonstrated recently (Wallner et al 1999;Schellings et al 2004;Sawada et al 2007;Pedretti et al 2010). Referring to these data and the tissue distribution and co-deposition Wndings of ED-A + Fn/ ASMA/B + Tn-C in chronic cardiac allograft rejection presented in this study, we suggest a functional contribution to the pathogenesis of CAV and CIF as the main signs of chronic cardiac rejection.…”

“…These clear Wndings speak well for an involvement of Tn-C variants in the development of CAV that is considered as a specialized form of classic atherosclerosis (Suzuki et al 2010). A crucial role of Tn-C during angiogenesis and also for the development of atherosclerotic lesions has been described recently (Wallner et al 1999;Schellings et al 2004;Sawada et al 2007). In accordance with our Wndings of a Tn-C deposition in areas of CIF, a contribution of the molecule to the recruitment of MyoFb in the diseased heart has been described (Schellings et al 2004).…”

“…Besides classical cECM components, adhesion-modulating molecules like Wbronectin, laminins or tenascin-C play important roles during physiologic and pathologic cardiac remodelling (Gabler et al 1996;Spinale et al 1998Spinale et al , 2002Kim et al 2000;Sawada et al 2007;Pawitan 2010;Franz et al 2010a, b). In particular, Wbronectin and tenascin-C could be shown to crucially participate in the regulation of cell-cell and cell-matrix interactions during heart development and in diVerent cardiac diseases (Farhadian et al 1995;Willems et al 1996;Kim et al 1999;Imanaka-Yoshida et al 2003Astrof and Hynes 2009;Pawitan 2010).…”

“…The role of tenascin-C (Tn-C) variants has not been investigated until now. Concerning classic atherosclerosis and the development of bypass graft stenosis, a pathogenetic relevance of Tn-C has been suggested (Wallner et al 1999;Sawada et al 2007). The molecule contributes to angiogenesis, recruitment of MyoFb and the regulation of cardiac myocyte-cECM interactions (reviewed in Schellings et al 2004).…”

Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization

“…In vascular disease, TN-C has been shown to accelerate neointimal formation (168, 169). The formation was reduced in TN-C-null mice, identifying a possible therapeutic target.…”