Nogo-A is a transmembrane protein with multiple functions in the central nervous system
(CNS), including restriction of neurite growth and synaptic plasticity. Thus far,
Nogo-A has been predominantly considered a cell contact-dependent ligand signaling
via cell surface receptors. Here, we show that Nogo-A can be secreted by cultured
cells of neuronal and glial origin in association with extracellular vesicles (EVs).
Neuron- and oligodendrocyte-derived Nogo-A containing EVs inhibited fibroblast spreading,
and this effect was partially reversed by Nogo-A receptor S1PR2 blockage. EVs purified
from HEK cells only inhibited fibroblast spreading upon Nogo-A over-expression. Nogo-A-containing
EVs were found in vivo in the blood of healthy mice and rats, as well as in human
plasma. Blood Nogo-A concentrations were elevated after acute stroke lesions in mice
and rats. Nogo-A active peptides decreased barrier integrity in an in vitro blood-brain
barrier model. Stroked mice showed increased dye permeability in peripheral organs
when tested 2 weeks after injury. In the Miles assay, an in vivo test to assess leakage
of the skin vasculature, a Nogo-A active peptide increased dye permeability. These
findings suggest that blood borne, possibly EV-associated Nogo-A could exert long-range
regulatory actions on vascular permeability.
