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