Unlike other neuronal counterparts, primary synaptic proteins are not known to be involved in vascular physiology. Here, we demonstrate that neurexins and neuroligins, which constitute large and complex families of fundamental players in synaptic activity, are produced and processed by endothelial and vascular smooth muscle cells throughout the vasculature. Moreover, they are dynamically regulated during vessel remodeling and form endogenous complexes in large vessels as well as in the brain. We used the chicken chorioallantoic membrane as a system to pursue functional studies and demonstrate that a monoclonal recombinant antibody against ␤-neurexin inhibits angiogenesis, whereas exogenous neuroligin has a role in promoting angiogenesis. Finally, as an insight into the mechanism of action of ␤-neurexin, we show that the anti-␤-neurexin antibody influences vessel tone in isolated chicken arteries. Our finding strongly supports the idea that even the most complex and plastic events taking place in the nervous system (i.e., synaptic activity) share molecular cues with the vascular system. angiogenesis ͉ vessel tone ͉ cell-to-cell adhesion ͉ nervous-vascular parallels ͉ synapses

Neurexins (Nrxs) have emerged as potential determinants of synaptic specificity, but little is known about their localization at central synapses. Here we show that Nrxs have a remarkably selective localization at distinct types of glutamatergic synapses and we reveal an unexpected ontogenetic regulation of Nrx expression at GABAergic synapses. Our data indicate that synapses are specified by molecular interactions that involve both Nrx-dependent and Nrx-independent mechanisms. We propose that differences in the spatio-temporal profile of Nrx expression may contribute to specify the molecular identity of synapses.

Neurexin (NRXN) and Neuroligin (NLGN) are trans-synaptic proteins involved in vascular biology. NRXN is encoded in long () and short () isoforms. We have shown that NRXNmodulates blood vessel development in synergy with VEGFA and associates with NLGN. On the other hand 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 NRXN, 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 NRXN and Tie2 physically associate in situ during vascular development. We used biochemical and cellular assays to prove that the synthetic 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 NRXN and Tie2 can be reciprocally immunoprecipated 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.