Abstract-Discoidin domain receptor 2 (DDR2) plays potential roles in the regulation of collagen turnover mediated by smooth muscle cells in atherosclerosis. How mechanical stretch affects the regulation of DDR2 in smooth muscle cells is not fully understood. We sought to investigate the cellular and molecular mechanisms of regulation of DDR2 by cyclic stretch in smooth muscle cells. Rat vascular smooth muscle cells grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles/min. Cyclic stretch significantly increased DDR2 protein and mRNA expression after stretch. Cyclic stretch also significantly increased DNA-protein binding activity of Myc-Max. Addition of SB203580, transforming growth factor-␤1 (TGF-␤1) monoclonal antibody, p38 small interfering RNA (siRNA), and c-myc siRNA 30 minutes before stretch inhibited the induction of DDR2 protein and abolished the DNA-protein binding activity induced by cyclic stretch. Cyclic stretch increased, whereas SB203580 abolished the phosphorylated p38 protein. Conditioned medium from stretched smooth muscle cells and exogenous administration of angiotensin II and TGF-␤1 recombinant proteins to the nonstretched cells increased DDR2 protein expression similar to that seen after stretch. In conclusion, cyclic mechanical stretch enhances DDR2 expression in cultured rat smooth muscle cells. The stretch-induced DDR2 is mediated by angiotensin II and TGF-␤1, at least in part, through p38 mitogen-activated protein kinase and Myc pathway. iscoidin domain receptor 1 (DDR1) and DDR2 are unusual receptor tyrosine kinases in that their ligands are fibrillar collagen rather than growth factor-like peptides. 1,2 DDR1 is expressed mainly in epithelial cells, whereas DDR2 is found in mesenchymal cells. 3 Evidences from the generation of DDR1 and DDR2-null mice and in vitro studies suggest that DDR can regulate cell proliferation and extracellular matrix remodeling mediated by matrix metalloproteinase (MMP) activities during normal development or pathological conditions. 4 -9 Prolonged stimulation of DDR2 has been associated with the upregulation of MMP-1 expression. 2 DDR2 also plays an important role in mediating hepatic stellate cells 8 and fibroblast 9 migration and proliferation by MMP-2-dependent mechanisms. Recently, Ferri et al showed that DDR 1 and DDR2 play potential roles in the regulation of collagen turnover mediated by vascular smooth muscle cells (VSMCs) in obstructive diseases of blood vessel. 10 However, the clear picture of DDR-signaling pathways is not known. 11 Transforming growth factor-␤ (TGF-␤) plays an important role in maintaining normal vessel wall structure, and that loss of this protective effect contributes to the development of atherosclerosis. 12 TGF-␤ inhibits smooth muscle proliferation, 13-15 inhibits VSMC migration, 16 and promotes the expression of an array of proteins that make up the contractile apparatus of the cell. [13][14][15][16] Reduced TGF-␤ activity is a common consequence of a range of environmental and ...