The ultrastructure of spinal cord perivascular spaces: Implications for the circulation of cerebrospinal fluid
Open accessAbstract
Perivascular spaces play a pivotal role in the exchange between cerebrospinal and interstitial fluids, and in the clearance of waste in the CNS, yet their precise anatomical components are not well described. The aim of this study was to characterise the ultrastructure of perivascular spaces and their role in the transport of fluid, in the spinal cord of healthy rats, using transmission electron microscopy. The distribution of cerebrospinal fluid tracers injected into the subarachnoid space was studied using light, confocal and electron microscopy. Perivascular spaces were found around arterioles and venules, but not capillaries, throughout the spinal cord white and grey matter. They contained fibroblasts and collagen fibres, and were continuous with the extracellular spaces of the surrounding tissue. At 5 min post injection, tracers were seen in the subarachnoid space, the peripheral white matter, the perivascular spaces, basement membranes, extracellular spaces of the surrounding tissue, and surprisingly, in the lumen of blood vessels, suggesting trans-vascular clearance. These findings point out an unrecognised outflow pathway for CNS fluids, with potential implications for volume regulation in health and disease states, but also clinically for the detection of CNS-derived biomarkers in plasma, the immune response and drug pharmacokinetics.
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Animal studies have shown communication between the subarachnoid CSF space and perivascular compartments of the brain and spinal cord.
“Previous animal studies have shown communication between the subarachnoid cerebrospinal fluid (CSF) space and perivascular compartments of the brain (6-10) and spinal cord (11).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [11]
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“We hypothesize that increased CSF protein content from tumor and blood breakdown products, combined with the dissection required in these cases, can also disrupt CSF drainage and perivascular Virchow-Robin spaces, 32 leading to local accumulation of CSF which adversely affects dural healing.”
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“The periarterial space and perivenous space are considered discontinued at the capillary level (23).”
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“Additionally, the model did not consider the presence of collagen fibres found in PVS (Lam et al. 2017), but rather modelled a uniform PVS permeability.”
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In vivo distribution of cerebrospinal fluid tracer in human upper spinal cord and brain stem
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“…moves through perivascular spaces in the parenchyma in a centripetal direction, not through the central canal from the fourth ventricle (11, 13), but how the tracer moves from the SAS to the deep regions of the spinal cord is not possible to assess with the spatial resolution in this study…”
BackgroundInfluentialThe effects of variation in the arterial pulse waveform on perivascular flow
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The meninges as a neuroimmune interface: structure, barriers and roles in CNS disease
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“However, other studies report tracer exchange between subarachnoid and perivascular compartments or fail to reproduce these morphological barriers, suggesting at least partial continuity between the subarachnoid space and perivascular spaces [65, 77, 78].”
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Self-citationAquaporin-4 expression and modulation in a rat model of post-traumatic syringomyelia
Berliner, J. A., Lam, M. A., Najafi, E., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-36538-x · Cited by 4 · see citing works
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Blending Established and New Perspectives on Choroid Plexus-CSF Dynamics
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Tachycardia and hypertension enhance tracer efflux from the spinal cord
Liu, S., Bilston, L. E., Stoodley, M. A., & Hemley, S. J. (2021) · Fluids and Barriers of the CNS · doi:10.1186/s12987-021-00279-8 · Cited by 3 · see citing works
“tracer confirmed that pathways of perivascular efflux are similar to inflow [8].”
BackgroundResultSelf-citationImpaired glymphatic flow as a potential driver of pain chronification
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Cerebrospinal and Interstitial Fluids: Production, Outflow, and Circulation
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Gadolinium-Based Imaging and the Study of Neurofluid Dynamics
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“Bucket” cerebrospinal fluid bulk flow: when the terrain disagrees with the map
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Brain Barriers in Normal Pressure Hydrocephalus: Mechanisms and Therapeutic Perspectives
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“8 We therefore turned to a nanoscale agent.”
Mechanisms and Applications of Conductive Biomaterials in Spinal Cord Injury Repair
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Nanoparticle Drug Delivery to Brain Tumors: From Intravenous to Intrathecal
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Spinal Cord Vasculature: General Anatomy and Physiology
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Incidental Neuroimaging Abnormalities in Patients with Headache Disorders
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Role of perivascular macrophages in a new experimental model of intracerebral aneurysms
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“The space between the outer wall of a cerebral blood vessel and the glia limitans is called the perivascular space (PVS) and it is fluid-rich (Lam et al. 2017).”
Bridging veins govern discrepancy of CSF efflux into dura mater in mice
Yan, L., Satyanarayanan, S. K., Huang, D., Qin, Y., Wu, D., Lai, J., Qin, D., & Su, H. (2026) · The Journal of Experimental Medicine · doi:10.1084/jem.20252556
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- Authors
- Lam, M. A., Hemley, S. J., Najafi, E., Vella, N. G. F., Bilston, L. E., & Stoodley, M. A.
- Affiliations
- Macquarie University (AU)
- Neuroscience Research Australia (AU)
- Corresponding author
- Lam, Magdalena A.
- Venue
- Scientific Reports
- Published
- 2017-10-10
- Volume
- 7
- Issue
- 1
- Pages
- 12924-12924
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5635033
- OpenAlex
- W2761340775
- Semantic Scholar
- 3eff02bebb984d6ed97aa88cea10cd4c4e2de842
- Cited by
- 71
- References
- 48
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 3 · 2023: 10 · 2022: 12 · 2021: 12 · 2020: 5 · 2019: 9 · 2018: 5
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- Funders
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- perivascular spaces, spinal cord, cerebrospinal fluid flow, ultrastructure, subarachnoid space, extracellular matrix, fibroblasts, collagen fibers, gray and white matter
- MeSH terms
- Animals, Blood Vessels, Cerebrospinal Fluid, Connective Tissue, Gold, Spinal Cord, Subarachnoid Space, Rats, Sprague-Dawley, Metal Nanoparticles
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