Critical role of dipeptidyl peptidase IV in neuropeptide Y-mediated endothelial cell migration in response to wounding.

Recently, we have discovered that neuropeptide Y (NPY), a sympathetic neurotransmitter, is also present in human umbilical endothelial cells (HUVECs), and is potently chemotactic and angiogenic by acting on one or several of Y1-Y5 receptors. In HUVECs, NPY is co-localized with dipeptidyl peptidase IV (DPPIV) which cleaves Tyr(1)-Pro(2) from NPY(1-36) to form NPY(3-36) resulting in the formation of a non-Y1 receptor agonist, which remains angiogenic. Presently we studied the effects of DPPIV's blockade using monoclonal antibodies (mAbs) on migration of HUVECs in response to NPY(1-36) or NPY(3-36) following cell wounding. Both peptides caused similar dose-dependent increases in cell migration (+80% at 0.1 nM) 12 h after wounding. DPPIV mAbs, E19 and E26, significantly reduced HUVEC's migration below that of the untreated cells, and blocked responses to NPY(1-36) but not NPY(3-36). Enhanced expression of DPPIV was found in the migrating cells and in cells with their protrusions at the edge of the wound (immunostaining and Western blot). Thus, DPPIV's expression is stimulated by endothelial wounding and its enzymatic activity is required for NPY-mediated chemotaxis. Furthermore, this suggests that non-Y1 receptors activated by NPY(3-36) (Y2, Y3 and/or Y5) mediate angiogenic effects of NPY.