Neurexin (NRXN) and Neuroligin (NLGN) are trans-synaptic proteins involved in vascular biology. NRXN is encoded in long (alpha) and short (beta) isoforms. We have shown that beta NRXN modulates blood vessel development in synergy with VEGFA and associates with NLGN. On the other hand alpha NRXN is also expressed in blood vessels but does not interact with NLGN or act in synergy with VEGFA, thus demonstrating a differential role. To find clues into the vascular functions of aNRXN, we chose a 7 aa motif that is part of its extracellular region and was formerly selected through a proteomic search for interactors of the vascular receptor Tie2. Next we (a) synthetized and modeled such peptide in order to determine its biological activity towards Tie2 in in vitro and in vivo angiogenesis assays and (b) evaluated if alpha NRXN and Tie2 physically associate in situ during vascular development. We used biochemical and cellular assays to prove that the synthetic alpha NRXN peptide (a) modulates the angiogenic phenotype of cultured endothelial cells and angiogenesis in vivo and (b) efficiently stimulates Tie2 phosphorylation and downstream mediators in endothelial cells. Moreover, we show that alpha NRXN and Tie2 can be reciprocally immunoprecipitated from chicken blood vessels at late stages of vascular development. These data have a double significance, i.e. provide a novel tool to modulate Tie2 and further suggest the involvement of the NRXN family of synaptic protein in the vascular system through their interaction with a fundamental vascular player. (C) 2013 Elsevier Inc. All rights reserved.