Distinct roles of ephrin-B2 forward and EphB4 reverse signaling in endothelial cells

Objective - The transmembrane ligand ephrin-B2 and its receptor tyrosine kinase EphB4 are specifically expressed on arterial and venous endothelial cells, respectively, and bidirectional signals mediated by both proteins play an important role in vascular development. However, how such bidirectional signals are required for cell-cell adhesion or repulsion remains unclear. Methods and Results - Using a cell line and sorted primary endothelial cells, we show that ephrin-B2 forward signaling through the EphB4 receptor inhibits cell adhesion, whereas EphB4 reverse signaling by the transmembrane ephrin-B2 ligand does not. Cell migration is also inhibited on immobilized ephrin-B2-Fc but not on EphB4-Fc protein. Conclusions - Ephrin-B2 forward signaling and EphB4 reverse signaling differentially affect cell adhesion and migration between arterial and venous endothelial cells.