Soluble CD146 is generated by ectodomain shedding of membrane CD146 in a calcium-induced, matrix metalloprotease-dependent process.

CD146 is a cell adhesion molecule localized at the endothelial junction and is involved in the control of cell-cell cohesion. In this study, we showed that calcium influx in human microvascular lung endothelial cells results in the loss of surface CD146 and the release of soluble CD146. This calcium-induced CD146 shedding could be prevented with inhibitors of matrix metalloproteases indicating a central role of matrix metalloproteases in this process. We also investigated if CD146 shedding influences vascular permeability. Endothelial cell monolayers cultured on filter membranes showed an increased permeability for albumin when stimulated with ionomycin. This calcium-induced increase in permeability was inhibited when CD146 shedding was prevented by a matrix metalloprotease inhibitor. Our data indicate that surface CD146 plays a central role in the regulation of vascular permeability and demonstrate that CD146 and matrix metalloproteases are potential targets to modify endothelial barrier function.