Objective-Vascular smooth muscle cell (VSMC) proliferation is an important component of atherosclerosis, restenosis after angioplasty and stent placement, and vein graft failure. Outside-in signaling from the cadherin:-catenin complex can increase transcription of the cell-cycle gene cyclin D1; however, its role in VSMC proliferation has only recently been considered. Methods and Results-We examined the involvement of R-cadherin and -catenin in VSMC proliferation in ballooninjured carotid arteries in vivo and aortic rings in vitro. The number of medial VSMCs positive for R-cadherin was significantly reduced by 32%Ϯ5%, 52%Ϯ10%, and 23%Ϯ2% at 0.25, 24, and 48 hours after injury in vivo, respectively. These changes in cadherin expression coincided with the detection of nuclear -catenin and elevated cyclin D1 expression. Furthermore, loss of R-cadherin expression was associated with medial VSMC proliferation. Inhibition of classical cadherin function with a HAV peptide and R-cadherin neutralizing antibodies significantly increased proliferation by 4.3Ϯ1.0-fold and 4.1Ϯ0.98-fold, and increased the number of cells with -catenin in the nucleus and expressing cyclin D1 in aortic rings. Conclusions-These results suggest that R-cadherin expression and -catenin signaling may be associated with increased cyclin D1 expression and VSMC proliferation and may therefore play an important role in vascular disease. Key Words: smooth muscle Ⅲ cadherin Ⅲ proliferation Ⅲ intimal thickening V ascular smooth muscle cell (VSMC) proliferation plays a key role in pathological processes characterized by neointimal thickening, such as atherosclerosis, vascular rejection, and restenosis after angioplasty and stent placement. 1,2 Balloon injury of arteries causes quiescent, medial cells to lose their differentiated, contractile phenotype and proliferate for up to 3 days. [3][4][5] After this first wave of medial VSMC proliferation, medial VSMCs migrate and appear in the intima 4 days after injury. A new proliferative wave is then observed in the intima, which peaks at Ϸ7 days. Increased synthesis of extracellular matrix components continues for at least 4 weeks after injury. 6 The cadherins are a family of transmembrane glycoproteins that mediate calcium-dependent homophilic cell-cell interaction. 7 One cell type can express multiple cadherins, and the expression pattern is cell type-specific. 8 The extracellular domain of cadherins promotes the cell-cell adhesion through a binding site, which contains a HAV motif in the classical type I cadherins. 9 The cytoplasmic region connects cadherins to the cytoskeletal components through the catenin proteins. In addition to serving a structural function by linking to the actin cytoskeleton, the classical cadherins act as signaling receptors that affect cell behavior, including cell proliferation, migration, and differentiation. 10,11 In the absence of Wnt signals, -catenin is either coupled to cadherins and the cytoskeleton at the plasma membrane or targeted for proteosomal degradation by the a...
