TGFβ1 suppresses vascular smooth muscle cell motility by expression of N-cadherin.

Neointimal formation in atheromatous blood vessels is associated with both growth factor-induced differentiation of smooth muscle cells and endothelial-to-mesenchymal transition. Transforming growth factor beta (TGFβ)-signaling is well known to play a critical role in the regulation of vessel remodeling as well as in atherosclerosis and restenosis. Here, we investigated the role of TGFβ1 and N-cadherin on the differentiation and migration of human vascular smooth muscle cells (VSMC). TGFβ1-treatment of cultured VSMC reduced their migratory activity as determined in cell migration assays. This reduced migration correlated with increased concentration of N-cadherin on mRNA and protein level. The TGFβ1-induced increase of N-cadherin was sensitive against pharmacological inhibition of the ALK5 TGFβ receptor and was accompanied by TGFβ1-induced expression of the transcription factor snail1. Activation of N-cadherin by using a HAV-containing peptide of N-cadherin also decreased the migration of VSMC. N-cadherin-mediated suppression of VSMC migration was associated with an increased activity of RhoA, which is activated by binding of the HAV peptide to N-cadherin. Our results demonstrate that TGFβ1 induces the differentiation of primary VSMC cells by Smad2/3-dependent up-regulation of the transcription factor snail1 and subsequently of N-cadherin, leading to inhibition of VSMC migration by RhoA-dependent modulation of the actin cytoskeleton.