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  • Review Article
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The neurovascular unit and systemic biology in stroke — implications for translation and treatment

Nature Reviews Neurology volume 18, pages 597–612 (2022)Cite this article

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Abstract

Ischaemic stroke is a leading cause of disability and death for which no acute treatments exist beyond recanalization. The development of novel therapies has been repeatedly hindered by translational failures that have changed the way we think about tissue damage after stroke. What was initially a neuron-centric view has been replaced with the concept of the neurovascular unit (NVU), which encompasses neuronal, glial and vascular compartments, and the biphasic nature of neural–glial–vascular signalling. However, it is now clear that the brain is not the private niche it was traditionally thought to be and that the NVU interacts bidirectionally with systemic biology, such as systemic metabolism, the peripheral immune system and the gut microbiota. Furthermore, these interactions are profoundly modified by internal and external factors, such as ageing, temperature and day–night cycles. In this Review, we propose an extension of the concept of the NVU to include its dynamic interactions with systemic biology. We anticipate that this integrated view will lead to the identification of novel mechanisms of stroke pathophysiology, potentially explain previous translational failures, and improve stroke care by identifying new biomarkers of and treatment targets in stroke.

Key points

  • According to the prevailing concept, the neurovascular unit (NVU) comprises multiple cell types from the neuronal, glial and vascular compartments but is functionally confined to cell-to-cell signalling within the CNS.

  • Novel pathways for brain–body communication, such as the glymphatic system and skull microchannels, have been identified, indicating that the brain is not the private compartment it was thought to be.

  • The NVU interacts with systemic biological processes and systems, including systemic metabolism, the peripheral immune system and the gut microbiota.

  • Factors such as age, temperature and the circadian clock not only affect the NVU but also profoundly modify the interactions between the NVU and systemic biology.

  • A conceptual extension of the NVU to include its interactions with systemic biology could provide a more accurate depiction of the biology after stroke.

  • This extended NVU framework might help to explain previous translational failures and improve stroke care by identifying novel biomarkers of and treatment targets in stroke.

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Fig. 1: Interactions between the neurovascular unit and systemic biology.
Fig. 2: Immunological niches and neuroimmune interfaces in the CNS.
Fig. 3: Microbiome–host crosstalk after stroke.

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Acknowledgements

We thank C. Benakis (Institute for Stroke and Dementia Research, University hospital, Ludwig-Maximilians-Universität München, Germany) and M. Merrow (Institute of Medical Psychology, Ludwig-Maximilians-Universität München, Germany) for critical revision of parts of the manuscript. S.T. is supported by a grant from the Corona Foundation. A.M.B. is supported by a visiting fellowship from the Einstein Foundation Berlin. All authors are supported by a grant from the Leducq Foundation.

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Authors and Affiliations

  1. Consortium International pour la Recherche Circadienne sur l’AVC (CIRCA) https://www.rdm.ox.ac.uk/about/our-divisions/investigative-medicine-division/the-leducq-circadian-network-1/circa

    Steffen Tiedt, Alastair M. Buchan, Martin Dichgans, Ignacio Lizasoain, Maria A. Moro & Eng H. Lo

  2. Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany

    Steffen Tiedt & Martin Dichgans

  3. Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Alastair M. Buchan

  4. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    Martin Dichgans

  5. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Martin Dichgans

  6. Department of Pharmacology and Toxicology, Complutense Medical School, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain

    Ignacio Lizasoain

  7. Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid, Spain

    Maria A. Moro

  8. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Eng H. Lo

  9. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Eng H. Lo

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  1. Steffen Tiedt
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  2. Alastair M. Buchan
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  3. Martin Dichgans
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  4. Ignacio Lizasoain
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  6. Eng H. Lo
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The authors contributed equally to all aspects of the article.

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Correspondence to Steffen Tiedt or Eng H. Lo.

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A.M.B. is a co-founder of Brainomix. The other authors declare no competing interests.

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Nature Reviews Neurology thanks D. Hermann, D. Michalski, S. Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Circadian rhythms

The ~24 h rhythmic temporal programmes found within almost all cells.

Glymphatic system

The cerebral glial-associated functional homologue of the peripheral lymphatic system that clears waste from the brain.

Perivascular spaces

The passageways surrounding cerebral microvessels that contribute to waste clearance.

Zeitgebers

Regular environmental signals that entrain circadian clocks.

Damage-associated molecular patterns

(DAMPS). The endogenous danger molecules that are released from damaged or dying cells.

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Tiedt, S., Buchan, A.M., Dichgans, M. et al. The neurovascular unit and systemic biology in stroke — implications for translation and treatment. Nat Rev Neurol 18, 597–612 (2022). https://doi.org/10.1038/s41582-022-00703-z

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