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

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    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).

    CAS  Article  Google Scholar 

  2. 2

    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).

    CAS  Article  Google Scholar 

  3. 3

    Hauser, S.L. & Oksenberg, J.R. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52, 61–76 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Trapp, B.D. & Nave, K.A. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247–269 (2008).

    CAS  Article  Google Scholar 

  5. 5

    Nikić, I. et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med. 17, 495–499 (2011).

    Article  Google Scholar 

  6. 6

    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).

    CAS  Article  Google Scholar 

  7. 7

    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).

    Article  Google Scholar 

  8. 8

    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).

    CAS  Article  Google Scholar 

  9. 9

    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).

    CAS  Article  Google Scholar 

  10. 10

    Fokman, J. & Brem, H. Angiogenesis and inflammation. in Inflammation: Basic Principles and Clinical Correlates. 2nd edn., 821–839 (Raven Press, New York, 1992).

  11. 11

    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).

    CAS  Article  Google Scholar 

  12. 12

    Costa, C., Incio, J. & Soares, R. Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis 10, 149–166 (2007).

    Article  Google Scholar 

  13. 13

    Carmeliet, P. Blood vessels and nerves: common signals, pathways and diseases. Nat. Rev. Genet. 4, 710–720 (2003).

    CAS  Article  Google Scholar 

  14. 14

    Vane, J.R. & Botting, R.M. Pharmacodynamic profile of prostacyclin. Am. J. Cardiol. 75, 3A–10A (1995).

    CAS  Article  Google Scholar 

  15. 15

    Buddeberg, B.S. et al. Behavioral testing strategies in a localized animal model of multiple sclerosis. J. Neuroimmunol. 153, 158–170 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Bareyre, F.M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat. Neurosci. 7, 269–277 (2004).

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    Menétrey, D., de Pommery, J. & Roudier, F. Propriospinal fibers reaching the lumber enlargement in the rat. Neurosci. Lett. 58, 257–261 (1985).

    Article  Google Scholar 

  19. 19

    Tessier-Lavigne, M. & Goodman, C.S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).

    CAS  Article  Google Scholar 

  20. 20

    Kirk, S.L. & Karlik, S.J. VEGF and vascular changes in chronic neuroinflammation. J. Autoimmun. 21, 353–363 (2003).

    CAS  Article  Google Scholar 

  21. 21

    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).

    CAS  Article  Google Scholar 

  22. 22

    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).

    CAS  Article  Google Scholar 

  23. 23

    Snider, W.D., Zhou, F.Q., Zhong, J. & Markus, A. Signaling the pathway to regeneration. Neuron 35, 13–16 (2002).

    CAS  Article  Google Scholar 

  24. 24

    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).

    CAS  Article  Google Scholar 

  25. 25

    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).

    CAS  Article  Google Scholar 

  26. 26

    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).

    CAS  Article  Google Scholar 

  27. 27

    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).

    CAS  Article  Google Scholar 

  28. 28

    Tammela, T. et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656–660 (2008).

    CAS  Article  Google Scholar 

  29. 29

    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).

    CAS  Article  Google Scholar 

  30. 30

    Liu, K. et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13, 1075–1081 (2010).

    CAS  Article  Google Scholar 

  31. 31

    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).

    Article  Google Scholar 

  32. 32

    Hino, T. et al. In vivo delivery of small interfering RNA targeting brain capillary endothelial cells. Biochem. Biophys. Res. Commun. 340, 263–267 (2006).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Toshihide Yamashita.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 (PDF 7952 kb)

Rights and permissions

Reprints and Permissions

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing