In experimental autoimmune encephalomyelitis (EAE), which is a model for multiple sclerosis, neurons in the corticospinal tract show axonal demyelination, which results in motor deficits. Inflammation can cause angiogenesis or the formation of new blood vessels. Muramatsu et al. (see also Brumm and Carmichael) found that in mice with localized EAE, an increase in angiogenesis preceded two events that can occur in EAE, fiber sprouting from neurons (which can lead to collateral formation and neuronal circuit rewiring to bypass lesions) and partial recovery from hindlimb motor performance defects. Cultured endothelial cells from mice with EAE released 6-keto prostaglandin F1 α (6-keto-PGF1-α), a stable metabolite of prostacyclin. Prostacyclin is a ligand for the type I prostaglandin receptor (IP receptor), which was detected in neurons in the hindlimb motor cortex by immunohistochemistry. Mouse cortical neurons extended longer neurites when cocultured with vascular endothelial cells than when cultured alone, an effect that was enhanced by the IP receptor agonist iloprost and attenuated by the IP receptor antagonist CAY10441 or by transfecting the vascular endothelial cells with siRNAs directed against prostaglandin synthase (PGIS) before coculturing them with the neurons. PGIS abundance increased after induction of the EAE lesion, and PGIS colocalized with CD105, a marker for proliferating endothelial cells. In vivo transfection of siRNAs directed against the IP receptor into neurons in the hindlimb motor cortex or PGIS siRNA into vascular endothelial cells decreased collateral formation in the corticospinal tract and spontaneous recovery of motor function after induction of EAE. In addition, intrathecal delivery of iloprost to increase IP receptor activity increased fiber sprouting in the corticospinal tract, cortical-evoked cord dorsum potentials (to measure the connection from the cerebral cortex to the corticospinal tract below the EAE lesion), and hindlimb motor performance, whereas treatment with the IP receptor antagonist CAY10441 had the opposite effects. Thus, blood vessels that form after the inflammatory insult in EAE release prostacyclin, which promotes fiber sprouting, neuronal circuit rewiring, and recovery of motor function.
R. Muramatsu, C. Takahashi, S. Miyake, H. Fujimura, H. Mochizuki, T. Yamashita, Angiogenesis induced by CNS inflammation promotes neuronal remodeling through vessel-derived prostacyclin. Nat. Med. 18, 1658–1664 (2012). [PubMed]
A. J. Brumm, S. T. Carmichael, Not just a rush of blood to the head. Nat. Med. 18, 1609–1610 (2012). [PubMed]