A novel function for cadherin 11/osteoblast-cadherin in vascular smooth muscle cells: Modulation of cell migration and proliferation

ObjectiveIntimal hyperplasia is a common cause of vein graft failure in cardiovascular surgery. The molecular basis for intimal hyperplasia remains poorly defined. We have previously identified, by gene chip analysis of vein grafts, increased messenger (mRNA) for the adhesion molecule cadherin 11/osteoblast-cadherin (CDH11). The function of CDH11 in vascular cells is unknown. The aim of the present study is to confirm CDH11 expression in vein grafts and characterize its role in vascular remodeling.MethodsCephalic vein interposition grafts were implanted in a canine model and harvested at predetermined time points. CDH11 protein expression was determined by immunohistochemistry. Early passage human coronary artery smooth muscle cells (SMCs) were used for in vitro studies. Real-time polymerase chain reaction was used to assess cellular CDH11 mRNA levels. CDH11 signaling was inhibited by either transfection with silencing RNA targeting CDH11 or with a blocking antibody to CDH11. Cellular migration was evaluated and cellular proliferation was assessed.ResultsExpression of CDH11 was increased in medial SMCs of vein grafts recovered at 7, 14, and 30 days after surgery compared with control veins from the same animals. In vitro CDH11 mRNA was up-regulated 1.8 ± 0.2-fold (P = .003) in SMCs after treatment with tumor necrosis factor-α. Cellular migration was attenuated by inhibition of CDH11 both with a blocking antibody (0.67 ± 0.09; P = .063) and gene knockdown mediated by small interfering RNA (0.67 ± 0.14; P = .036). SMC proliferation decreased by 3.1-fold (P = .006) in the presence of CDH11-blocking antibody. Knockdown of CDH11 mediated by small interfering RNA resulted in a 1.3-fold (P = .018) decrease in proliferation.ConclusionsCDH11 is up-regulated in SMC in vivo and in vitro as part of the response to injury. Inhibition of CDH11 decreases SMC migration and proliferation, two pathogenic effectors of intimal hyperplasia.

Clinical RelevanceIntimal hyperplasia, the pathologic process of intimal thickening that occurs when veins are used as conduit for arterial reconstruction, limits the patency of all bypass grafts. At the time of grafting, a sequence of signaling events are initiated that induce intimal hyperplasia. Silencing the expression of specific genes could interrupt the sequence of events leading to the formation of intimal hyperplasia. Through gene chip analysis of an experimental model of intimal hyperplasia, we have identified induced genes, including cadherin 11/osteoblast-cadherin (CDH11). CDH11 is a 120-kDa cell surface glycoprotein involved in cell signaling. Inhibition of CDH11 signaling in vitro attenuates vascular smooth muscle migration and proliferation, the pathologic hallmarks of intimal hyperplasia.