The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease
Open accessAbstract
The concept of the neurovascular unit (NVU), formalized at the 2001 Stroke Progress Review Group meeting of the National Institute of Neurological Disorders and Stroke, emphasizes the intimate relationship between the brain and its vessels. Since then, the NVU has attracted the interest of the neuroscience community, resulting in considerable advances in the field. Here the current state of knowledge of the NVU will be assessed, focusing on one of its most vital roles: the coupling between neural activity and blood flow. The evidence supports a conceptual shift in the mechanisms of neurovascular coupling, from a unidimensional process involving neuronal-astrocytic signaling to local blood vessels to a multidimensional one in which mediators released from multiple cells engage distinct signaling pathways and effector systems across the entire cerebrovascular network in a highly orchestrated manner. The recently appreciated NVU dysfunction in neurodegenerative diseases, although still poorly understood, supports emerging concepts that maintaining neurovascular health promotes brain health.
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BBB breakdown and dysfunction is associated with cerebral blood flow (CBF) reductions and dysregulation, contributing to neurological deficits.
“which is associated with cerebral blood flow (CBF) reductions and dysregulation (269-271, 318), contributing to neurological deficits.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [271]
The Alzheimer’s disease and Parkinson disease sections report BBB permeability changes and CBF reductions, and the Parkinson disease section links reduced CBF with cognitive dysfunction (page numbers unavailable). But the paper does not establish that BBB breakdown causes the flow changes or neurological deficits; the Frontotemporal dementia section describes mice with increased BBB permeability but no reduction in resting CBF or cerebrovascular reactivity. (LLM, conf=0.83)
Experimental — accuracy not yet measuredEnergy substrates are consumed by the brain 'on the fly' from blood via transport across the BBB, as the brain lacks a reservoir to store fuel for use when needed.
“Energy substrates are consumed by the brain 'on the fly' from blood via transport across the BBB, as the brain lacks a reservoir to store fuel for use when needed (271).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [271]
The Introduction (page unavailable) says the brain lacks a fuel reservoir and receives energy substrates, primarily oxygen and glucose, “on the fly” through its blood supply. The section “The neurovascular unit: beyond blood flow” describes BBB transporters generally, but does not specify transport of those energy substrates across the BBB; that added detail is not established by the cited passages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe pattern of cerebral blood vessels follows the major brain circuits tasked with sensation, memory, and motion, suggesting that the cerebrovascular system plays an important role in normal CNS functioning.
“The pattern of cerebral blood vessels follows the major brain circuits tasked with sensation, memory, and motion suggesting that the cerebrovascular system plays an important role in normal CNS functioning (271, 318, 682).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [271]
In “Neurovascular interactions through the ages” (page unavailable), the paper says vascular density differs across brain regions and is associated with functional activity, supporting a role for blood vessels in normal brain function. It does not establish that the pattern of vessels follows circuits for sensation, memory, and motion; the “Neurovascular coupling” section also notes that vascular and neuronal topology do not overlap in the neocortex. (LLM, conf=0.83)
Experimental — accuracy not yet measuredDifferent cell types of the neurovascular unit (NVU) including vascular cells, glia, and neurons contribute to regulation of BBB permeability, neurovascular coupling, cell-matrix interactions, neurotransmitter turnover, and angiogenesis and neurogenesis.
“Different cell types of the neurovascular unit (NVU) including vascular cells [e.g., endothelium and mural cells including pericytes and smooth muscle cells (SMCs)], glia (e.g., astrocytes, microglia), and neurons contribute to regulation of BBB permeability, neurovascular coupling, cell-matrix interactions, neurotransmitter turnover, and angiogenesis and neurogenesis (270, 271, 692, 693)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [271]
The sections “Where do we go from here?” and “The neurovascular unit: beyond blood flow” describe contributions of neurons, astrocytes, endothelial cells and mural cells to neurovascular coupling, BBB integrity, matrix-related signaling and vascular and neural development (page numbers not supplied). The copy does not establish the claimed role in neurotransmitter turnover; it also mentions microglia without showing their contribution to the listed functions. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDelivery of energy substrates can be adjusted on demand through modulation of neurovascular coupling or via neuronal signaling to astrocytes.
“This process can be adjusted on demand either through modulation of neurovascular coupling15–17 or via neuronal signaling to astrocytes18.”
From Energy paradox in REM sleep: balancing supply and consumption in brain metabolism (2026) · cites this paper as [15]
In the mammalian brain, cerebral arteries, arterioles, and capillaries supply CNS circuits with blood in response to neuronal stimuli by increasing the rate of CBF and oxygen delivery, a mechanism known as neurovascular coupling.
“In the mammalian brain, cerebral arteries, arterioles, and capillaries supply CNS circuits with blood in response to neuronal stimuli by increasing the rate of CBF and oxygen delivery, a mechanism known as neurovascular coupling (271, 319).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [271]
GM1 reduced damage of the brain system caused by trauma and ischemia, promoted repair of injured neurons, and improved cognition of AD patients following intraventricular injection.
“GM1, an important lipid component in the brain, especially in neurons,[ 16 ] reduced the damage of brain system caused by trauma and ischemia, promoted the repair of injured neurons and improved the cognition of AD patients following intraventricular injection.[ 13 , 17 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [13]
The Alzheimer’s disease section discusses amyloid-β, vascular dysfunction, and ischemic injury, but does not address GM1 treatment. Searches for GM1, gangliosides, intraventricular injection, and neuronal repair found no passage supporting the claimed reduction in injury or improvement in cognition. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn vivo application of GM1 is largely limited by the negligible amount of GM1 that can cross the blood-brain barrier to access its target.
“But its in vivo application is largely limited by the negligible amount of GM1 that can cross the BBB to access its target.[ 13 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [13]
The section “The neurovascular unit: beyond blood flow” discusses BBB transport and permeability, but not GM1 or its ability to cross the barrier. Searches for GM1, ganglioside, and BBB delivery found no passage addressing the claimed limitation on GM1’s in vivo use; the supplied passages have no page numbers. (LLM, conf=0.74)
Experimental — accuracy not yet measured
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References 253 · Cited by 2,480
- Authors
- Iadecola, C.
- Affiliations
- Weill Cornell Medicine (US)
- Corresponding author
- Iadecola, Costantino
- ORCID
- Iadecola, Costantino
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 96
- Issue
- 1
- Pages
- 17-42
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5657612
- OpenAlex
- W2759050422
- Cited by
- 2,480
- References
- 253
- Citations by year
- 2026: 394 · 2025: 340 · 2024: 315 · 2023: 316 · 2022: 296 · 2021: 293 · 2020: 269 · 2019: 161 · 2018: 90 · 2017: 2 · 2015: 2 · 2013: 1 · 2012: 1
- FWCI
- 13.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R37-NS89323, R01-NS34179, R01-NS95441, R01-NS37853, R01-NS100447)
- Feil Family Foundation
- Fondation Leducq
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- neurovascular unit, neurovascular coupling, signaling pathways, neurodegenerative diseases, brain health, stroke
- MeSH terms
- Neurovascular Coupling, Astrocytes, Brain, Health, Humans, Models, Neurological, Neurons, Signal Transduction, Neurodegenerative Diseases
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