Fig. 4.

Proposed role of the endothelial P2Y₂R in paracellular leukocyte diapedesis. Tissue damage or infection causes the local release of inflammatory signals that upregulate the endothelial P2Y₂R as well as adhesion molecules required for leukocyte adhesion to vascular endothelium. These leukocytes begin migrating toward chemoattractants released from the damaged/infected site and, in so doing, release a burst of ATP from their leading edge [239]. We hypothesize that ATP released from adherent leukocytes activates the endothelial P2Y₂R causing trafficking or relocation of this receptor to endothelial adherens junctions, possibly through interaction of the P2Y₂R with Src, VEGFR-2, and the actin-binding protein, filamin A [22, 89, 100]. We also hypothesize that endothelial P2Y₂R relocation to adherens junctions assists in the transient disruption of endothelial junctions and escorts leukocytes to endothelial borders for paracellular diapedesis, possibly through association of the P2Y₂R with the α_Vβ₃ integrin. This integrin is known to form a complex with the P2Y₂R [23] and with JAM-1 [276], a junctional adhesion molecule in endothelial cells that interacts with the leukocyte integrin, LFA-1, and is important for both leukocyte adhesion and diapedesis [277]