CCN notch signaling in vascular smooth muscle cells: good or bad?

In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Shimoyama et al1 demonstrates that neointimal formation after vascular injury is enhanced in CCN3 knockout mice, suggesting that CCN3 suppresses neointimal thickening. In addition, the results from in vitro approaches further demonstrate that CCN3 inhibits vascular smooth muscle cell (VSMC) growth and migration, and the inhibitory effect of CCN3 on VSMC growth is mediated in part by the activation of Notch signaling. The inhibitory effect of CCN3-Notch signaling on VSMC proliferation is interesting; however, it appears opposite or contradictory to most previous reports of Notch signaling in VSMC (Figure). The activation of Notch receptor results from 2 types of proteolytic cleavages by ADAM10 (or TACE) metalloprotease and -secretase complex, which release Notch intracellular domain from the cell membrane. The Notch intracellular domain enters the nucleus and interacts with DNA-binding protein recombination signal-binding protein for immunoglobulin kappa J region, leading to the transcriptional activation of Notch target gene, including Hes and Hey.2,3 Sakata et al4 have reported that neointimal formation was significantly reduced in Hey2 / mice. It has also been reported that both Hey1 and Hey2 overexpression in VSMC increased cell proliferation by reducing p21waf1 or p27kip1 expression.5 In addition, a recent study further showed that the neointimal formation after carotid artery ligation was decreased 70% in systemic Notch 1 heterozygous-deficient (N1 / ) mice or VSMCspecific Notch 1 heterozygous-deficient (smN1 / ) mice compared with wild-type control mice. Smooth muscle cells derived from N1 / or smN1 / mice had decreased proliferation and increased apoptosis compared with wild-type controls.6 These results indicate that the activation of Notch 1 in VSMC promotes VSMC proliferation and neointimal formation after vascular injury and suggests a “proproliferation” role of Notch-Hey signaling in VSMC.