Angiogenesis induced by CNS inflammation promotes neuronal remodeling through vessel-derived prostacyclin


Angiogenesis is a prominent feature of central nervous system (CNS) disease and has roles in both the continued promotion of inflammation and the subsequent repair processes. Here we report that prostacyclin (or prostaglandin I2 (PGI2)) derived from new vessels promotes axonal remodeling of injured neuronal networks after CNS inflammation. In a localized model of experimental autoimmune encephalomyelitis (EAE), new vessels formed around the inflammatory lesion, followed by sprouting of adjacent corticospinal tract (CST) fibers. These sprouting fibers formed a compensatory motor circuit, leading to recovery of motor function. Capillary endothelial cell–derived prostacyclin bound to its receptor, the type I prostaglandin receptor (IP receptor), on CST neurons, promoting sprouting of CST fibers and contributing to the repair process. Inhibition of prostacyclin receptor signaling impaired motor recovery, whereas the IP receptor agonist iloprost promoted axonal remodeling and motor recovery after the induction of EAE. These findings reveal an important function of angiogenesis in neuronal rewiring and suggest that prostacyclin is a promising molecule for enhancing functional recovery from CNS disease.

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Figure 1: Rewiring of hindlimb corticospinal axons is preceded by neovascularization during EAE.
Figure 2: Vascular endothelial cell–derived prostacyclin promotes neurite elongation in corticospinal neurons through cAMP signaling.
Figure 3: Prostacyclin and IP receptor promote neuronal rewiring in response to EAE.
Figure 4: Knockdown of PGIS in vascular endothelial cells delays recovery of motor function in EAE.
Figure 5: Treatment with iloprost improves the EAE-induced deficit in motor function.


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The authors are grateful to N. Takakura, H. Kidoya and M. Ueno for helpful comments and M. Niwa and S. Nakagawa for technical advice on culturing of endothelial cells. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (23122512) from the Japan Society for the Promotion of Sciences to R.M. and the Core Research for Evolutional Science and Technology from Japan Science and Technology Agency to T.Y.

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R.M. performed all experiments, with the exception of the portions indicated below. C.T. supported immunohistochemical analyses. C.T. and S.M. helped with in vitro experiments. H.M. and H.F. provided the autopsy samples from individuals with multiple sclerosis. R.M. and T.Y. designed the experiments. T.Y. coordinated and directed the project and wrote the manuscript.

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Correspondence to Toshihide Yamashita.

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The authors declare no competing financial interests.

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Muramatsu, R., Takahashi, C., Miyake, S. et al. Angiogenesis induced by CNS inflammation promotes neuronal remodeling through vessel-derived prostacyclin. Nat Med 18, 1658–1664 (2012).

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