The expression of ephrinB2 in endothelial cells delineates their arterial phenotype and is a prerequisite for the development of the embryonic vasculature. Whereas the role of ephrinB2 in the microvasculature has been studied extensively, its expression and function in adult arteries is not well understood. To this end, we found that ephrinB2 is most abundantly expressed in endothelial cells at arteriosclerosis-prone sites of the mouse aorta. Moreover, its expression was increased in growing collateral arterioles after occlusion of the main feeding artery - a process which is referred to as arteriogenesis. Both, atherosclerosis and arteriogenesis are at least partially triggered by a local increase in circumferential wall tension hence stretch - a biomechanical force that controls the expression of ephrinB2 through activation of the transcription factor AP-1. Interestingly, in all vascular beds studied, ephrinB2 was localized on the luminal surface of the endothelial cells enabling its interaction with circulating leukocytes. In this context, monocytes were shown to express EphB receptors on their surface which facilitates their transmigration through an ephrinB2- expressing endothelial cell monolayer. The exposure of monocytes to ephrinB2 enhances protrusion formation and the release of pro-inflammatory cytokines which may affect the remodelling of the vessel wall during arteriogenesis and atherosclerosis. Conversely, binding of EphB receptors to endothelial cell ephrinB2 triggers the expression of pro-inflammatory adhesion molecules such as VCAM-1 in these cells. Taken together our data establishes stretch, i.e. an increase in wall tension, as an important trigger of endothelial cell ephrinB2 expression during vascular remodelling processes thereby putting this molecule into a new functional context of facilitating monocyte extravasation and pro-inflammatory activity.