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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lucas, S.M., Rothwell, N.J. & Gibson, R.M. The role of inflammation in CNS injury and disease. Br. J. Pharmacol. 147, S232–S240 (2006).
Harel, N.Y. & Strittmatter, S.M. Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nat. Rev. Neurosci. 7, 603–616 (2006).
Hauser, S.L. & Oksenberg, J.R. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52, 61–76 (2006).
Trapp, B.D. & Nave, K.A. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247–269 (2008).
Nikić, I. et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med. 17, 495–499 (2011).
DeLuca, G.C., Ebers, G.C. & Esiri, M.M. Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts. Brain 127, 1009–1018 (2004).
Black, J.A., Liu, S., Hains, B.C., Saab, C.Y. & Waxman, S.G. Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE. Brain 129, 3196–3208 (2006).
Kerschensteiner, M. et al. Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis. J. Exp. Med. 200, 1027–1038 (2004).
Jackson, J.R., Seed, M.P., Kircher, C.H., Willoughby, D.A. & Winkler, J.D. The codependence of angiogenesis and chronic inflammation. FASEB J. 11, 457–465 (1997).
Fokman, J. & Brem, H. Angiogenesis and inflammation. in Inflammation: Basic Principles and Clinical Correlates. 2nd edn., 821–839 (Raven Press, New York, 1992).
Kirk, S., Frank, J.A. & Karlik, S. Angiogenesis in multiple sclerosis: is it good, bad or an epiphenomenon? J. Neurol. Sci. 217, 125–130 (2004).
Costa, C., Incio, J. & Soares, R. Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis 10, 149–166 (2007).
Carmeliet, P. Blood vessels and nerves: common signals, pathways and diseases. Nat. Rev. Genet. 4, 710–720 (2003).
Vane, J.R. & Botting, R.M. Pharmacodynamic profile of prostacyclin. Am. J. Cardiol. 75, 3A–10A (1995).
Buddeberg, B.S. et al. Behavioral testing strategies in a localized animal model of multiple sclerosis. J. Neuroimmunol. 153, 158–170 (2004).
Bareyre, F.M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat. Neurosci. 7, 269–277 (2004).
Courtine, G. et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat. Med. 14, 69–74 (2008).
Menétrey, D., de Pommery, J. & Roudier, F. Propriospinal fibers reaching the lumber enlargement in the rat. Neurosci. Lett. 58, 257–261 (1985).
Tessier-Lavigne, M. & Goodman, C.S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).
Kirk, S.L. & Karlik, S.J. VEGF and vascular changes in chronic neuroinflammation. J. Autoimmun. 21, 353–363 (2003).
Holley, J.E., Newcombe, J., Whatmore, J.L. & Gutowski, N.J. Increased blood vessel density and endothelial cell proliferation in multiple sclerosis cerebral white matter. Neurosci. Lett. 470, 65–70 (2010).
Uesugi, N., Muramatsu, R. & Yamashita, T. Endothelin promotes neurite elongation by a mechanism dependent on c-Jun N-terminal kinase. Biochem. Biophys. Res. Commun. 383, 509–512 (2009).
Snider, W.D., Zhou, F.Q., Zhong, J. & Markus, A. Signaling the pathway to regeneration. Neuron 35, 13–16 (2002).
Hannila, S.S. & Filbin, M.T. The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury. Exp. Neurol. 209, 321–332 (2008).
Jung, S., Donhauser, T., Toyka, K.V. & Hartung, H.P. Propentofylline and iloprost suppress the production of TNF-α by macrophages but fail to ameliorate experimental autoimmune encephalomyelitis in Lewis rats. J. Autoimmun. 10, 519–529 (1997).
Makita, T., Sucov, H.M., Gariepy, C.E., Yanagisawa, M. & Ginty, D.D. Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons. Nature 452, 759–763 (2008).
Dray, C., Rougon, G. & Debarbieux, F. Quantitative analysis by in vivo imaging of the dynamics of vascular and axonal networks in injured mouse spinal cord. Proc. Natl. Acad. Sci. USA 106, 9459–9464 (2009).
Tammela, T. et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656–660 (2008).
Vavrek, R., Girgis, J., Tetzlaff, W., Hiebert, G.W. & Fouad, K. BDNF promotes connections of corticospinal neurons onto spared descending interneurons in spinal injured rats. Brain 129, 1534–1545 (2006).
Liu, K. et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13, 1075–1081 (2010).
Ueno, M., Hayano, Y., Nakagawa, H. & Yamashita, T. Intraspinal rewiring of the corticospinal tract requires target-derived neurotrophic factor and compensates lost function after brain injury. Brain 135, 1253–1267 (2012).
Hino, T. et al. In vivo delivery of small interfering RNA targeting brain capillary endothelial cells. Biochem. Biophys. Res. Commun. 340, 263–267 (2006).
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.
The authors declare no competing financial interests.
About this article
Cite this article
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). https://doi.org/10.1038/nm.2943
XQ-1H promotes cerebral angiogenesis via activating PI3K/Akt/GSK3β/β-catenin/VEGF signal in mice exposed to cerebral ischemic injury
Life Sciences (2021)
International Immunology (2020)
Current Tissue Microenvironment Reports (2020)
Journal of Neuroimmune Pharmacology (2020)