Reactive astrocytes facilitate vascular repair and remodeling after stroke

Abstract

Brain injury causes astrocytes to assume a reactive state that is essential for early tissue protection, but how reactive astrocytes affect later reparative processes is incompletely understood. In this study, we show that reactive astrocytes are crucial for vascular repair and remodeling after ischemic stroke in mice. Analysis of astrocytic gene expression data reveals substantial activation of transcriptional programs related to vascular remodeling after stroke. In vivo two-photon imaging provides evidence of astrocytes contacting newly formed vessels in cortex surrounding photothrombotic infarcts. Chemogenetic ablation of a subset of reactive astrocytes after stroke dramatically impairs vascular and extracellular matrix remodeling. This disruption of vascular repair is accompanied by prolonged blood flow deficits, exacerbated vascular permeability, ongoing cell death, and worsened motor recovery. In contrast, vascular structure in the non-ischemic brain is unaffected by focal astrocyte ablation. These findings position reactive astrocytes as critical cellular mediators of functionally important vascular remodeling during neural repair.

References 75

1. 1.

   Allegra Mascaro AL, Conti E, Lai S, Di Giovanna AP, Spalletti C, Alia C, Panarese A, Scaglione A, Sacconi L, Micera S, (2019 ). Combined rehabilitation promotes the recovery of structural and functional features of healthy neuronal networks after stroke. Cell Rep. 28, 3474–3485.e6.

   Not in our library10.1016/j.celrep.2019.08.062

2. 2.

   Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea TM, Kawaguchi R, Coppola G, Khakh BS, Deming TJ, and Sofroniew MV (2016 ). Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200.

   Not in our library10.1038/nature17623

3. 3.
   Decoding the Transcriptional Response to Ischemic Stroke in Young and Aged Mouse Brain · 2020

   Not checked
4. 4.

   Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, and Newman EA (2010 ). Glial and neuronal control of brain blood flow. Nature 468, 232–243.

   Not in our library10.1038/nature09613

5. 5.

   Baskin YK, Dietrich WD, and Green EJ (2003 ). Two effective behavioral tasks for evaluating sensorimotor dysfunction following traumatic brain injury in mice. J. Neurosci. Methods 129, 87–93.

   Not in our library10.1016/s0165-0270(03)00212-7

6. 6.

   Boisvert MM, Erikson GA, Shokhirev MN, and Allen NJ (2018 ). The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep. 22, 269–285.

   Not in our library10.1016/j.celrep.2017.12.039

7. 7.

   Broughton BRS, Reutens DC, and Sobey CG (2009 ). Apoptotic mechanisms after cerebral ischemia. Stroke 40, e331–e339.

   Not in our library10.1161/strokeaha.108.531632

8. 8.

   Brown CE, Li P, Boyd JD, Delaney KR, and Murphy TH (2007 ). Extensive turnover of dendritic spines and vascular remodeling in cortical tissues recovering from stroke. J. Neurosci 27, 4101–4109.

   Not in our library10.1523/jneurosci.4295-06.2007

9. 9.
   Transcriptomics of post-stroke angiogenesis in the aged brain · 2014

   Not checked
10. 10.

    Burda JE, and Sofroniew MV (2014 ). Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81, 229–248.

    Not in our library10.1016/j.neuron.2013.12.034

11. 11.

    Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH, and Sofroniew MV (1999 ). Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23, 297–308.

    Not in our library10.1016/s0896-6273(00)80781-3

12. 12.

    Carmeliet P, and Tessier-Lavigne M (2005 ). Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200.

    Not in our library10.1038/nature03875

13. 13.

    Clark TA, Sullender C, Kazmi SM, Speetles BL, Williamson MR, Palmberg DM, Dunn AK, and Jones TA (2019a ). Artery targeted photothrombosis widens the vascular penumbra, instigates peri-infarct neovascularization and models forelimb impairments. Sci. Rep 9, 2323.

    Not in our library10.1038/s41598-019-39092-7

14. 14.

    Clark TA, Sullender C, Jacob D, Zuo Y, Dunn AK, and Jones TA (2019b ). Rehabilitative training interacts with ischemia-instigated spine dynamics to promote a lasting population of new synapses in peri-infarct motor cortex. J. Neurosci 39, 8471–8483.

    Not in our library10.1523/jneurosci.1141-19.2019

15. 15.

    Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, and Barres BA (2018 ). Normal aging induces A1-like astrocyte reactivity. Proc. Natl. Acad. Sci. USA 115, E1896–E1905.

    Not in our library10.1073/pnas.1800165115

16. 16.

    Davis GE, and Senger DR (2005 ). Endothelial extracellular matrix: Biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ. Res 97, 1093–1107.

    Not in our library10.1161/01.res.0000191547.64391.e3

17. 17.
    GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists · 2009

    No notice
18. 18.

    Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, and Sofroniew MV (2004 ). Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci 24, 2143–2155.

    Not in our library10.1523/jneurosci.3547-03.2004

19. 19.

    Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson L, Truelsen T,; Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) and the GBD Stroke Experts Group (2014 ). Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet 383, 245–254.

    Not in our library10.1016/s0140-6736(13)61953-4

20. 20.

    Freitas-Andrade M, Raman-Nair J, and Lacoste B (2020 ). Structural and functional remodeling of the brain vasculature following stroke. Front. Physiol 11, 948.

    Not in our library10.3389/fphys.2020.00948

21. 21.

    Gӧbel J, Engelhardt E, Pelzer P, Sakthivelu V, Jahn HM, Jevtic M, Folz-Donahue K, Kukat C, Schauss A, Frese CK, (2020 ). Mitochondria-endoplasmic reticulum contacts in reactive astrocytes promote vascular remodeling. Cell Metab. 31, 791–808.e8.

    Not in our library10.1016/j.cmet.2020.03.005

22. 22.

    Garcia ADR, Doan NB, Imura T, Bush TG, and Sofroniew MV (2004 ). GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat. Neurosci 7, 1233–1241.

    Not in our library10.1038/nn1340

23. 23.

    Griffin JM, Fackelmeier B, Fong DM, Mouravlev A, Young D, and O’Carroll SJ (2019 ). Astrocyte-selective AAV gene therapy through the endogenous GFAP promoter results in robust transduction in the rat spinal cord following injury. Gene Ther. 26, 198–210.

    Not in our library10.1038/s41434-019-0075-6

24. 24.

    Guttenplan KA, Stafford BK, El-Danaf RN, Adler DI, Münch AE, Weigel MK, Huberman AD, and Liddelow SA (2020 ). Neurotoxic reactive astrocytes drive neuronal death after retinal injury. Cell Rep. 31, 107776.

    Not in our library10.1016/j.celrep.2020.107776

25. 25.

    Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, Gundersen GA, Skare Ø, Laake P, Klungland A, Thorén AE, Burkhardt JM, Ottersen OP, and Nagelhus EA (2011 ). Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc. Natl. Acad. Sci. USA 108, 17815–17820.

    Not in our library10.1073/pnas.1110655108

26. 26.

    Hartmann DA, Berthiaume A-A, Grant RI, Harrill SA, Koski T, Tieu T, McDowell KP, Faino AV, Kelly AL, and Shih AY (2021 ). Brain capillary pericytes exert a substantial but slow influence on blood flow. Nat. Neurosci Published online February 18, 2021..

    Not in our library10.1038/s41593-020-00793-2

27. 27.

    Hayakawa K, Nakano T, Irie K, Higuchi S, Fujioka M, Orito K, Iwasaki K, Jin G, Lo EH, Mishima K, and Fujiwara M (2010 ). Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab 30, 871–882.

    Not in our library10.1038/jcbfm.2009.257

28. 28.

    Hayakawa K, Pham LDD, Katusic ZS, Arai K, and Lo EH (2012 ). Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery. Proc. Natl. Acad. Sci. USA 109, 7505–7510.

    Not in our library10.1073/pnas.1121146109

29. 29.

    He F, Sullender C, Zhu H, Williamson MR, Li X, Zhao Z, Jones TA, Xie C, Dunn AK, and Luan L (2020 ). Multimodal mapping of neural activity and cerebral blood flow reveals long-lasting neurovascular dissociations after small-scale strokes. Sci. Adv 6, eaba1933.

    Not in our library10.1126/sciadv.aba1933

30. 30.

    Heithoff BP, George KK, Phares AN, Zuidhoek IA, Munoz-Ballester C, and Robel S (2021 ). Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain. Glia 69, 436–472.

    Not in our library10.1002/glia.23908

31. 31.

    Hellström M, Gerhardt H, Kalén M, Li X, Eriksson U, Wolburg H, and Betsholtz C (2001 ). Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol 153, 543–553.

    Not in our library10.1083/jcb.153.3.543

32. 32.

    Henderson-Toth CE, Jahnsen ED, Jamarani R, Al-Roubaie S, and Jones EAV (2012 ). The glycocalyx is present as soon as blood flow is initiated and is required for normal vascular development. Dev. Biol 369, 330–339.

    Not in our library10.1016/j.ydbio.2012.07.009

33. 33.

    Howarth C, Sutherland B, Choi HB, Martin C, Lind BL, Khennouf L, LeDue JM, Pakan JMP, Ko RWY, Ellis-Davies G, (2017 ). A critical role for astrocytes in hypercapnic vasodilation in brain. J. Neurosci 37, 2403–2414.

    Not in our library10.1523/jneurosci.0005-16.2016

34. 34.

    Hu NY, Chen YT, Wang Q, Jie W, Liu YS, You QL, Li ZL, Li XW, Reibel S, Pfrieger FW, (2020 ). Expression patterns of inducible cre recombinase driven by differential astrocyte-specific promoters in transgenic mouse lines. Neurosci. Bull 36, 530–544.

    Not in our library10.1007/s12264-019-00451-z

35. 35.

    Kang M, and Yao Y (2020 ). Basement membrane changes in ischemic stroke. Stroke 51, 1344–1352.

    Not in our library10.1161/strokeaha.120.028928

36. 36.

    Kim SY, Hsu JE, Husbands LC, Kleim JA, and Jones TA (2018 ). Coordinated plasticity of synapses and astrocytes underlies practice-driven functional vicariation in peri-infarct motor cortex. J. Neurosci 38, 93–107.

    Not in our library10.1523/jneurosci.1295-17.2017

37. 37.

    Kisler K, Nikolakopoulou AM, Sweeney MD, Lazic D, Zhao Z, and Zlokovic BV (2020 ). Acute ablation of cortical pericytes leads to rapid neurovascular uncoupling. Front. Cell. Neurosci 14, 27.

    Not in our library10.3389/fncel.2020.00027

38. 38.

    Kubotera H, Ikeshima-Kataoka H, Hatashita Y, Allegra Mascaro AL, Pavone FS, and Inoue T (2019 ). Astrocytic endfeet re-cover blood vessels after removal by laser ablation. Sci. Rep 9, 1263.

    Not in our library10.1038/s41598-018-37419-4

39. 39.

    Kutuzov N, Flyvbjerg H, and Lauritzen M (2018 ). Contributions of the glycocalyx, endothelium, and extravascular compartment to the blood-brain barrier. Proc. Natl. Acad. Sci. USA 115, E9429–E9438.

    Not in our library10.1073/pnas.1802155115

40. 40.

    Lee J-K, Kim J-E, Sivula M, and Strittmatter SM (2004 ). Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J. Neurosci 24, 6209–6217.

    Not in our library10.1523/jneurosci.1643-04.2004

Cited by papers we hold 2

• Beyond the gut: decoding the gut–immune–brain axis in health and disease · 2025
  No notice
• Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin · 2022
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.